REVIEWS

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Contribution of macronutrients to
obesity: implications for precision
nutrition
Rodrigo San-​Cristobal 1, Santiago Navas-​Carretero 2,3,4 ✉,
Miguel Ángel Martínez-​González 3,4,5,6, José María Ordovas 7,8,9

and José Alfredo Martínez1,2,3,4

Abstract | The specific metabolic contribution of consuming different energy-​yielding
macronutrients (namely, carbohydrates, protein and lipids) to obesity is a matter of active
debate. In this Review, we summarize the current research concerning associations between
the intake of different macronutrients and weight gain and adiposity. We discuss insights into
possible differential mechanistic pathways where macronutrients might act on either appetite or
adipogenesis to cause weight gain. We also explore the role of dietary macronutrient distribution
on thermogenesis or energy expenditure for weight loss and maintenance. On the basis of the
data discussed, we describe a novel way to manage excessive body weight; namely, prescribing
personalized diets with different macronutrient compositions according to the individual’s
genotype and/or enterotype. In this context, the interplay of macronutrient consumption with
obesity incidence involves mechanisms that affect appetite, thermogenesis and metabolism,
and the outcomes of these mechanisms are altered by an individual’s genotype and microbiota.
Indeed, the interactions of t­he genetic make-​up and/or microbiota features of a person with
specific macronutrient intakes or dietary pattern consumption help to explain individualized
responses to macronutrients and food patterns, which might represent key factors for
comprehensive precision nutrition recommendations and personalized obesity management.

The increase in the prevalence of obesity is associated
with a concomitant rise in the incidence of metabolic
disorders1. Obesity is defined as an excessive body
weight due to the dysfunctional accumulation of energy
reserves as fat depots2. The expansion of adipose tissue
in obesity is predominantly caused by a sustained energy
imbalance owing to elevated calorie intake and/or
a decline in energy expenditure2. A chronic excess of
body fat promotes unbalanced energy homeostasis as
well as the onset of impairments in glucose, lipid and
protein metabolism3 that can trigger chronic low-​grade
inflammation and cardiometabolic diseases4 in addition
to psychological stress, including low self-​esteem and
other diverse physiopathological disturbances5.
Present day globalization has resulted in sociocul-
tural shifts that have altered dietary and lifestyle habits6,
including increases in the consumption of convenience,
ultraprocessed and fast foods, which are energy-​dense7,8.
✉e-​mail: snavas@unav.es In addition, increased urbanization has also promoted
https://doi.org/10.1038/ sedentary lifestyles with a subsequent reduction in
s41574-020-0346-8 energy expenditure9,10. Some authors, however, have
suggested that the downward trend in physical activity is
not the only cause of the obesity epidemic. For example,
some individuals with obesity expend similar amounts
of energy from physical activity as lean controls11.
These findings highlight the importance of focusing
on food intake and food composition as well as energy
expenditure from exercise.
The importance of physical activity and its interac-
tion with diet in relation to energy balance needs to be
acknowledged in the context of obesity as both contrib-
ute to weight stability12. For example, an individual’s food
intake should be assessed in view of their energy expen­
diture, whereby any increase in physical activity needs
to be matched with a concurrent increase in energy
intake. Diet and physical activity have inter-​related
effects on energy balance and body weight manage-
ment, whereby energy flux, which is defined as the rate
at which energy from food is used for metabolic pur-
poses or stored in tissues12, modifies the dynamic fuel
homeostasis of the organism13. Therefore, variations in
the type or intensity of physical activity can modulate

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Key points
• Body weight and adiposity rely on energy equilibrium driven by energy-​yielding
macronutrient intake and energy expenditure under strict neuroendocrine control.
• Complex energy homeostasis interactions between carbohydrates, lipids and
proteins (dietary quantity and quality) follow the interpretation of their separate roles
on fuel metabolism.
• The intake of simple sugars and some saturated fatty acids has adverse effects on
body adiposity, while protein and fibre consumption seem to beneficially modulate
satiety and energy metabolism-​related processes.
• Personal genetic background and gut microbiota features contribute to explaining
some metabolic inter-​individual differences to macronutrient consumption.
• Advances in understanding metabolism pathways and hormonal control depending
on macronutrient intake involved in energy utilization are needed for precision and
public health nutrition.
energy metabolism, not only by a negative energy bal-
ance but by altering substrate utilization14 or by mod-
ifying the energy intake signals15. With these data in
mind, some authors, but not all, have hypothesized that
sedentarism could have a worse effect on an individual’s
chances of developing obesity than eating large amounts
of processed food16. Furthermore, individuals with obe-
sity can achieve similar levels of energy expenditure as
those who are lean through different means (mainly they
need less exercise to reach the same energy expenditure),
but still remain obese11. Indeed, this energy expenditure
from exercise is not enough to favour adipose tissue
mobilization and thus weight loss.
The combination of a sedentary lifestyle and
unhealthy dietary habits has been proposed as one of
the most important drivers of overweight and obe-
sity17,18. The unfavourable effects of this adverse milieu
are more apparent and critical in groups with lower
socio­economic status, where the consumption of inex-
pensive foods, which are typically rich in fats and simple
carbohydrates, is enhanced19. Therefore, it is important
to identify dietary-​related solutions in the ‘food system’
that can diminish the prevalence of obesity and related
complications19. Such solutions could include the pro-
motion of healthy dietary habits and diets that are rich
in whole grains, legumes, nuts, fruits, vegetables and
unsaturated fatty acids, in addition to advising against
Author addresses
1
Precision Nutrition and Cardiometabolic Health, IMDEA-​Food Institute (Madrid Institute
for Advanced Studies), Campus of International Excellence (CEI) UAM+CSIC, Spanish
National Research Council, Madrid, Spain.
2
Centre for Nutrition Research, University of Navarra, Pamplona, Spain.
3
CIBERobn, Centro de Investigacion Biomedica en Red Area de Fisiologia de la Obesidad
y la Nutricion, Madrid, Spain.
4
IdisNA, Navarra Institute for Health Research, Pamplona, Spain.
5
Department of Preventive Medicine and Public Health, School of Medicine, University
of Navarra, Pamplona, Spain.
6
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
7
Nutrition and Genomics Laboratory, JM-​USDA Human Nutrition Research Center on
Aging at Tufts University, Boston, MA, USA.
8
Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional
de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
9
Nutritional Genomics of Cardiovascular Disease and Obesity Fundation IMDEA Food,
Campus of International Excellence, Spanish National Research Council, Madrid, Spain.
the consumption of refined grains and food with added
sugars, processed meats and saturated fats19. With such
solutions in mind, several governments are implement-
ing legislative actions to promote the availability of
healthier food products20,21 and the use of taxes to dis-
courage the consumption of simple sugars, saturated fats
and trans fatty acids21.
Current approaches for the prevention and treat-
ment of unhealthy weight gain rely on dietary caloric
restriction, which is frequently accompanied with a spe-
cific physical activity plan22; however, the interactions
between dietary intake and physical activity need further
study to understand the importance of their interactions
for weight management23. In this context, social and cul-
tural factors related to consumerism, materialism and
hedonism seem important upstream determinants (that
is, ‘the causes of the causes’) of the global obesity pan-
demic7. In addition, epidemiological studies have shown
that, aside from accounting for calories, the quality of the
diet and macronutrient distribution can be important in
the control of obesity24.
Beyond diet, other factors are associated with an
individual’s predisposition to obesity, including genet-
ics, epigenetics, metagenomics, perinatal feeding, sleep
deprivation, endocrine disruption, adverse effects of
therapeutics, environment and adiposity-​driven clin-
ical history (that is, the conjoint factors that lead to
obesity, in which adipose tissue has an essential role)25.
Moreover, there are inter-​individual differences related
to the progression of obesity or cardiometabolic dis-
eases that could be a result of differences in genetics, gut
microbiota composition and dietary habits. For exam-
ple, some people with obesity have been described as
‘metabolically healthy obese’ and some lean individuals
have been found to be ‘metabolically unhealthy’25. These
findings warrant further investigation to individualize
nutritional recommendations and interventions26. In
this Review, we summarize the process involved in the
metabolism of macronutrients (carbohydrates, lipids
and proteins) with a focus on the physiological and
neuroendocrine aspects. We also discuss the claimed
associations between macronutrients and obesity in the
context of factors such as genetics and the microbiome
composition.
Body weight and macronutrients
The identification of the physiological pathways that
control energy metabolism and body weight regulation
has been the subject of extensive research and debate
(Fig. 1) . Several theories that describe the effects of
macronutrients or macronutrient-​derived molecules
(including glucose, amino acids and fatty acids) on
body weight regulation have been proposed. These the-
ories explain the regulatory elements that are involved
in food intake and the development of obesity27. One
such theory is the glucostatic theory28, which states that
the regulation of hunger and satiety perception depends
on the glucose availability and utilization in specific
brain regions. This notion was proposed to under-
lie the short-​term regulation of appetite. Conversely,
long-​term control of energy balance and body weight
would involve lipostatic mechanisms28. In this context,
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the overall quality of carbohydrates, which is defined
as their solid or liquid status, how processed they are,
their fibre content and the glycaemic index is strongly
related to sweetness perception, responses of blood lev-
els of glucose and hunger suppression. All these traits
influence the risk of obesity or cardiometabolic events in
random­ized nutritional trials29 and epidemiologic stud-
ies30–33. Additional nutritional investigations have sug-
gested that some specific dietary fatty acids and amino
acids might have a role in energy balance34–36.
Energy homeostasis is integrated into a complex
gut–neuroendocrine network that diminishes the effect

Hypothalamus
• POMC and CART
• NPY and AgRP
• Circadian rhythms
• mTOR and/or AMPK

Efferent signals
• Neuropeptides
• Lipid turnover
• UCP1
• Nervous system
signalling

Food Afferent signals

• Gastrointestinal hormones
(PYY, GLP1, CCK, ghrelin,
insulin and leptin)
• Peptides Brown and/or
• Metabolites beige adipocytes
• Nutrients • Thermogenesis

Liver
Stomach

Pancreas

Gut microbiota
• SCFA Intestine

White adipocyte
• Fat and/or
energy storage

Skeletal muscle
• Energy expenditure
• Thermogenesis
Energy expenditure
Physical activity
Thermogenesis
Carbohydrates
Energy intake

Proteins
Lipids

BMR

Lipogenesis Lipolysis

DNA

Fig. 1 | Key metabolic mechanisms on body weight regulation. Food intake induces the production of a range of signals,
including gut hormones, peptides, metabolites and the nutrients contained in food, which affect different mechanisms in
the brain for activating processes in the body, such as appetite control, or thermogenesis and vital functions, which are as
simple as breathing, or maintaining the metabolic functions will use the nutrients and food ingested to induce fermentative
processes and synthesize metabolites, such as short-​chain fatty acids (SCFAs). All these processes correspond to the
blue lines, which lead to energy intake. Also, in the brain, efferent signals are produced and sent to different tissues for
promoting thermogenesis and/or energy storage, which correspond to the red lines, and contribute to energy expenditure.
BMR, basal metabolic rate; mTOR, mechanistic target of rapamycin.

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Ileal brake
The delay in gastric emptying
and small intestinal transit
induced by the presence
of certain nutrient solutions
or products in the ileum.
of short-​term energy balance variations on fat mass37–39.
With this in mind, one group has emphasized the impor-
tance of glucose kinetics in the plasma, which involve
the rise and fall of glucose levels that lead to the regula-
tion of hunger40. Studies that analysed long-​term body
weight regulation support this theory as they found asso-
ciations between normal glycaemic control, weight gain
and weight regain following energy restriction41. This
theory remains disputed, however, as other investiga-
tors have proposed different models to explain energy
balance and body weight regulation. For example, the
role of amino acids in the plasma (which are associated
with anorexigenic hormones that promote satiety and
increase diet-​induced thermogenesis)36 in the regulation
of hunger and satiety has been explored35.
Other research has focused on the role of adipose
tissue reserves in the regulation of body weight42. This
notion was supported by the discovery of leptin, which
provided an endocrine mechanism by which the adipose
tissue communicates with the hypothalamic regulatory
centres of satiation43. Furthermore, it has been hypoth-
esized that body weight and composition result from
interconnected homeostatic pathways44 that involve the
regulation of energy intake by the central and peripheral
nervous system, nutrient turnover and thermogenesis in
muscle, liver and adipose reserves44. In this context, rele-
vant afferent signals that arrive at the brainstem, as well
as endocrine and nervous efferent signals, are elicited
to maintain the energy balance for a physiological con-
trol of the body composition (Fig. 1). In addition to these
and other behavioural models45, new perspectives about
body weight regulation have updated the ‘fat-​stat’ theory,
which proposes that people are programmed to accu-
mulate a certain amount of body fat and to eat enough
to maintain the level of fat determined by a hypothetical
‘set point’ mechanism46.
The feedback control of energy intake and expen­
diture detailed by the aforementioned theories remains
controversial, as does the involvement of social, environ-
mental and other hedonistic and learned eating habits47.
The current availability of processed, highly palatable
foods48 (which usually have a high energetic density)
might have led to the dysregulation of the food reward
signal that promotes hyperphagia49 and the homeostatic
regulation of energy balance as these process are sus-
ceptible to heritable and acquired alterations that mod-
ify taste responsiveness, food preferences and reward
pathways50. As such, the sugar and fat content of foods
seems to have an important role in the modifications
of the reward network51. However, more studies are
needed to elucidate the effect of specific sugar compo-
sition and sources52–54. In addition, specific fatty acids
act as precursors of endocannabinoids and related struc-
tural derivatives that can contribute to the regulation of
eating behaviour through neuroendocrine signalling55,
while protein can participate in satiety and thermogenic
processing involved in food intake and utilization36,56.
One further aspect that has scarcely been investigated
is the chronobiology of energy homeostasis57. Dietary
fats and carbohydrates interact with the circadian clock
system, where specific fatty acids and glucose can influence
behavioural and molecular circadian chronorhythmicity,
which affects the central nervous system, non-​central
nervous system and peripheral organs by altering energy
status sensors58. This hypothesis is in line with glucostatic
theory. Furthermore, a high intake of simple carbohydrates
and saturated fatty acids can lead to obesity by disrupt-
ing molecular plasticity and neuro­genesis in the brain
regions59 that are involved in the monitoring of stored
sugars and fats in the periphery60. The circadian oscilla-
tions in metabolism are influenced by the daily patterns of
feeding and energy utilization, which affect the circadian
alignment between the endocrine system (leptin, insulin
or ghrelin secretion) and sleeping patterns58. Similarly,
sleep alterations (such as sleep deprivation) can alter the
endocrine circadian rhythm that affects the satiety and/or
hunger sensations as well as other aspects related to sub-
jective well-​being involving dopamine and other neuro­
transmitters through different macronutrient-​related
mechanisms61.
Furthermore, the extent of metabolic flexibility,
which is the ability to shift fuel selection between glu-
cose and fatty acids in skeletal muscle and adipose tissue,
seems to contribute to fat accumulation in some circum-
stances62. In addition, physical activity has been shown
to have a key role in improving metabolic flexibility in
people with obesity. The authors reported that, follow-
ing an increase in dietary fat, individuals with obesity
had enhanced muscular fatty acid oxidation, which was
not observed before the commencement of an exercise
regime period63. In addition, bile acid signalling and gut
microbiota composition might have a role64 in weight
management, as might the ileal brake, which effects meta­
b­olic homeostasis and appetite suppression as a result of
dietary lipid, carbohydrate and protein consumption65.
Peptides in the gut and vagal afferent neuron signalling
have also been implicated in the regulation of glucose
metabolism and food intake66. Depending on food (that
is, energy) abundance or scarcity, nutrient-​s ensing
pathways and mitochondrial activity are differently
influenced by the specific intracellular and extracellular
availability of macronutrients and macronutrient deriv-
atives (including sugars, lipids and amino acids) through
hormonal signals that engage anabolism and storage or
catabolism and utilization67. Interestingly, understand-
ing ‘personal’ signatures, such as genetic make-​up and
gut microbiota composition, could help us understand
the different inter-​individual inputs caused by dietary
macronutrient composition on weight gain.
Indeed, the precise role of dietary lipids and carbo-
hydrates in the obesity epidemic is controversial due to
inconsistent data that result from the lack of specifically
designed trials68 and the presence of compensatory inter-
actions with regard to the supply of macronutrients69 or
genetic predisposition for obesity in some populations70.
Interventional studies have been unable to definitively
clarify the difference between the effects of lipid or
carbo­hydrate intake on weight management. While
some studies suggest that a reduction in dietary fat con-
tent can promote a modest weight reduction71, others
suggest that low-​carbohydrate diets are more effective
for body weight reduction with specific benefits on
blood profiles of lipids and glucose72. There are findings,
however, that suggest that the kilocalories coming from
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different macronutrients do not count equally towards
energy management and weight control, but rather
interactions between fats, carbohydrates and proteins
make it difficult to interpret the individual contribution
of each source on energy usage72–74. In any case, aside
from the amount of fat or carbohydrate in the diet,
growing evidence suggests that the quality of dietary fat
(natural unsaturated fat instead of trans or saturated
fat)73 and the quality of dietary carbohydrates (with a
preference for solid, high-​fibre, low-​glycaemic index and
whole grain foods)33 are stronger determinants of the
effects of diet on weight maintenance than the amount of
each macronutrient in the diet74. Researchers generally
accept, however, that a diet enriched with high-​quality
carbohydrates with a low glycaemic index and high fibre
content is associated with a reduced incidence of obe-
sity74. Conversely, simple carbohydrate-​rich foods (such
as sugar-​sweetened beverages) have often been associ-
ated with increased obesity risk75 due to the potential
effects of sucrose and fructose on leptin synthesis. To
date, two mechanisms for fructose-​induced obesity have
been proposed: some have suggested it occurs via an
increase in energy intake and reduced energy expendi-
ture76, whereas others have proposed the existence of a
‘fat switch’, leading to fat storage, insulin resistance and
the metabolic syndrome77.
The relationship between dietary fat and body fat has
also been a controversial issue34,78. The higher energy
density of fat when compared with other macronutrients
has fuelled the belief that lipid consumption is the major
driver of weight gain. There is, however, evidence that
the replacement of dietary saturated fats with sugars is
associated with excessive adiposity and some associated
metabolic complications79. In addition, other studies
have shown that the consumption of unsaturated oils
might not induce obesity80,81, suggesting that fat qual-
ity is more important than quantity (for example, as is
observed in those who follow Mediterranean dietary
patterns82 or consume tree nuts83). Some have pro-
posed a role for intestinal microbiota colonization that
is dependent on the make-​up of dietary lipids, proteins
and carbohydrates to partly explain these outcomes84.
The association between macronutrient homeo-
stasis and appetite regulation has an important role in
energy expenditure, the different sources of oxidation
(fat, carbohydrates or protein) and the accumulation of
adipose tissue. Furthermore, the proportion of protein
in the diet affects appetite regulation and satiety induc-
tion. For instance, interventional studies have exhibited
the dietary effects of high-​protein diets on appetite sup-
pression56,85. Diets that were rich in protein resulted in a
reduction in hunger perception and an increase in energy
expenditure and levels of β-​hydroxybutyrate85, which
could contribute to the appetite decrease56. In addition,
these authors analysed the joint effect of a high-​protein
diet in the presence or absence of carbo­hydrate in a res-
piratory chamber after a glycogen-​lowering exercise, and
found a statistically significant reduction in hunger
and respiratory quotient, suggesting an increase in fat
oxidation. After blood samples were taken, participants
entered the respiratory chamber, where they were pro-
vided with all necessary food items depending on the
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phase assigned (normal protein or high protein) and
consumption was controlled. The high-​protein diet
had no carbohydrates at all, while the normal protein
diet had carbohydrates that were either refined or unre-
fined. However, some long-​term longitudinal analyses
have reported that the intake of animal protein has unfa-
vourable effects on weight maintenance after 5 years
of follow-​up86. Indeed, consuming 250 g per day of
meat would produce an additional annual weight gain
of 422 g, compared with an isocaloric diet with lower
meat content86. Increasing vegetable protein intake at the
expense of animal protein and sugars therefore might be
a method of combating overweight and obesity at the
population level24. These results highlight the impor-
tance of the proportions of macronutrients, but fur-
ther research should focus also on protein sources and
glycaemic index for weight maintenance87,88.
The use of glycaemic index, protein and fat content
in weight loss diets has also produced varied results,
where some studies have shown that energy restriction
might be the main driver of weight lowering71,89, while
in others a low fat intake47 or a high protein intake pro-
duced more benefits for weight loss or maintenance90.
Weight regain after weight loss shows inter-​individual
variability and depends on macronutrient intake, where
protein and fibre seem to have important roles that affect
inflammatory processes, adipokine secretion, cellular
stress, extracellular matrix remodelling and other related
phenomena91,92. Indeed, controlled trials and epidemio­
logical analyses suggest a more adverse role for simple
sugars than for fats in obesity. However, the specific
involvement of liquid versus solid sugars, the glycaemic
load or fructose content and the different implications of
unsaturated and saturated fatty acid intake needs further
research76,79,93. In particular, research is needed as lauric
acid, myristic acid and other fatty acids might elicit dif-
ferential signals in energy homeostasis as well as some
specific proteins and amino acids94.
Regulation of homeostasis
Body weight and composition depend on the balance
between calorie intake from energy-​yielding macro­
nutrients (carbohydrates, lipids and proteins) and com-
ponents of energy expenditure (basal metabolic rate,
physical activity and dietary-​induced thermogenesis).
In this balance, dietary macronutrient distribution and
physical activity and/or exercise patterns are involved
(Supplementary Table 1) but so is the unique efficiency
of energy metabolism of each individual, which in turn
is controlled by their own genetic and/or epigenetic
make-​up and microbiota-​related mechanisms2,47.
Weight status and adiposity are also associated with
fuel inputs from macronutrients and alcohol, in addi-
tion to the unique nutrient turnover and thermogenic
processes of each person and by individual meta­
bolic features of energy utilization and homeostasis95.
Physiological combustion values for proteins, carbo-
hydrates and lipids have been conventionally assumed
as 4 kcal/g, 4 kcal/g and 9 kcal/g, respectively, once the
pump calorimeter values and the main losses in urine
and faeces plus the expenses for urea synthesis are
accounted for96,97. The ATP efficiency (KJ–ATP) can
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Weende approach
range from 99–153 KJ–ATP for proteins to 96 KJ–ATP
The calculation of carbohydrate for some fatty acids or 91 KJ–ATP for glucose, while
from the known content of fat, the estimated diet-​induced thermogenesis is 20–30%,
protein and fibre of a food. 5–10% and 0–3% for proteins, carbohydrates and lipids,
Nutrigenetics
respectively96. The determination of the nutritional and
The science that identifies and energy values of food macronutrients relies on proxi-
characterizes gene variants mal methodologies, some of which have been used for
associated with differential a long time such as the Weende approach. Alternative
response to nutrients and
approaches involve very specific strategies concerning
relates this variation to diverse
disease states.
the chemical analysis of complex or simple sugars and
individual amino or fatty acids as well as animal trials for
assessing biological outcomes such as glycaemic index,
protein quality or fat consumption97.
The specific macronutrient contribution to weight
gain and body fat accumulation has been a matter of
controversy during the past few decades. However, there
are several trials and physiological studies that have
advanced the evaluation of the quality of macronutri-
ents and have defined their role in homeostasis main-
tenance, with different involvements of carbohydrate
(Box 1), lipids (Box 2) and proteins (Box 3).
Genetics and nutrient utilization
Nutrigenetics provides support to the notion of more
precise dietary recommendations in clinical practice
and public health that are based on the unique genetic
background of the individual98. The implementation
of this knowledge allows for a better understanding of
the differential responses to dietary interventions and
is helping to determine population clusters with differ-
ent nutrient requirements99. Screening and analysing
individuals for specific genetic variants will provide
information on the most suitable macronutrient distri-
bution, which will enable researchers to understand the
Box 1 | carbohydrate metabolism
Carbohydrates encompass different types of molecules from complex polysaccharides
and starches to simple sugars, such as monosaccharides or disaccharides, and diverse
fibres with variable energy values and digestibility191. These structural differences result
in variations in their physical properties, digestibility and functions97. The influence of
carbohydrates on food intake and satiety is mediated by several pathways related to
gut–brain neuroendocrine signalling, intestinal fermentation (induced by short-​chain
fatty acids or other metabolites) and the physical and/or chemical properties
of carbohydrates (such as bulking and viscosity), as well as insulin sensitivity192–194.
Appetite and satiety regulation in relation to the maintenance of blood levels
of glucose is regulated by insulin and glucagon, which are secreted by the pancreas
and result in glycogenesis and glycogenolysis, respectively. Indeed, the effect
of carbohydrates, including fibre, on the postprandial release of satiety-​related
gastrointestinal peptides (CCK, ghrelin, GLP1, PYY and GIP) has been demonstrated38.
Monosaccharides and disaccharides, such as sucrose, fructose and lactose, are the
most common sugars consumed by humans and their role in appetite and food reward
is associated with sweet taste receptors195,196. Fibre and starch are the most complex
carbohydrate structures present in the diet. The role of fibre in satiation and appetite
in relation to weight maintenance has been thoroughly investigated due to its low
energetic density (2 kcal/g) and satiating effects derived from hydration capacity,
which provide viscosity and bulking that affect mechanoreceptors in the gut, increasing
motility and acting as the main substrate for gut microbiota161,193,194,197. Researchers
have also described a role for high sugar consumption on reduced insulin sensitivity76,
while the influence of low carbohydrate intake on energy expenditure remains
controversial47. However, in the past few years, glycaemic index and/or load has been
used to determine the quality of carbohydrate intake and induced effects on insulin
response30, expounding the involvement of the food glycaemic index on food intake
and the regulation of body weight198–200.
different personalized responses to carbohydrates, lipids
and protein intake and enable health care professionals
to provide recommendations for nutritional counsel-
ling100 (Table 1). Currently, the predictive value of most
of the obesity-​related genetic variants is low by them-
selves. However, synergetic effects between genes and
their interactions with the environment, such as nutri-
tional intake, have been shown to putatively mediate the
effect on obesity and related phenotypes, which makes
the interpretation difficult in some cases101. Further
research and the application of new omic techniques
are needed to improve our knowledge of phenotypic
nutrient responsiveness102 and allow the use of genetic
and combinatory scores103 to screen and cluster the indi-
viduals who are at risk of developing obesity104. Indeed,
an individual’s genetic background is recognized as a
driver to explain the inter-​individual differences con-
cerning weight gain and obesity susceptibility as well as
the weight loss and weight regain after an energy-
​restricted intervention. Therefore, despite the need for
additional validation studies, valuable findings have been
published that describe the interaction of macronutrient
consumption in carriers of diverse single-​nucleotide
polymorphisms in genes that regulate processes such as
appetite thermogenesis and lipid metabolism100.
Investigations that have addressed the relationship
between specific polymorphisms and appetite responses
that depend on energy intake in men in the overweight
BMI category found that variants of LEP and FTO were
associated with the perceived feeling of fullness after the
consumption of fat, sugar or protein and therefore could
have a role in the control of food and energy intake105.
These results are in line with a study that showed that
compared with participants with no risk allele people
who had the risk allele for the FTO variant rs9939609
reported lower subjective fullness, a higher consumption
of energy-​dense food and consumed 350 kcal above the
recommended amounts, suggesting that individuals with
genetic risk had impaired central nervous system satiety
processing106. These data are in contrast with the results
of a meta-​analysis that reported a statistically significant
reduction in total energy intake for each copy of the FTO
risk allele107. Further to these data, some genome-​wide
association studies found that the rs17782313 and
rs17700633 variants of MC4R were related to an increased
intake of dietary fat and total energy, and carriers had a
higher ten-​year increase in BMI than non-​carriers108.
Together these studies provide important insights
into the genetic effects on energy intake. However, a
review reported a lack of consistency concerning the
association between the FTO and MC4R genotypes
with specific macronutrients (carbohydrate or fat) and
total energy intake for weight management109, which
highlights the need for further research.
Indeed, some inter-​personal differences in the adipos-
ity response to carbohydrate consumption are genotype-
​dependent and might be affected by the type and quality
of consumed sugars. Therefore, a high intake of carbo­
hydrates (>49% of total daily food intake) in carriers
of the rs1042714 variant was associated with increased
BMI110. Another study that investigated carbohydrate
consumption found that the risk of obesity was associated
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Box 2 | lipid metabolism
Lipids have a high energy density and their consumption might directly influence food
intake and energy expenditure201 as well as energy metabolism via indirect mechanisms,
which has an effect on obesity and associated disorders202. Lipids have a central role in
fuel accumulation and an important function in the endocrine system203. The role of
lipids in appetite and satiety regulation involves hedonic processes and palatability
of foods through sensorial receptors and chemoreceptors203. Currently, research is
focused on associations between fat quality and fatty acid saturation rather than the
amount of fat consumed82. An increase in the dietary omega-6 fatty acid to omega-3
fatty acid ratio has been associated with an increased risk of weight gain and adiposity
through mechanisms of adipogenesis, adipose tissue homeostasis, adipose browning
and inflammation; this increase is mediated by the brain–gut–adipose axis via eicosanoid
metabolites and hyperactivity of the cannabinoid system204. In this context, modulatory
roles for high fat consumption on gastrointestinal regulatory feeding pathways related
to fat deposition affects lipid absorption and utilization, blunting satiation signals and
promoting excess body weight, where CCK, ghrelin, GLP1 and other neuropeptides
are related to appetite and/or satiation205. Additionally, medium-​chain triglycerides,
conjugated linoleic acid and polyunsaturated fatty acids elicit different satiating and
gastric emptying effects203. Moreover, polyunsaturated fatty acids have an important
role in the regulation of body composition; they result in directed changes on energy
intake and expenditure and alterations in lipid turnover and adipogenesis, which are
mediated by the neuroendocrine system in addition to appetite and satiation control206.
Furthermore, some dietary lipids might stimulate thermogenic functions by promoting
brown and beige fat development202. Lipids also play a role in food texture that may
make a food more desirable. However, fats might also display undesirable palatability
properties and unpleasant flavours, which may lead to rejection of a food and therefore
interfere with energy intake rather than postprandial mechanisms207. The rise in obesity
associated with fat consumption has also been related to induced food preferences208 and
reduced substrate oxidation, ketone bodies sparing glucose metabolism mechanisms
and shifts in lipolytic and/or lipogenic activities or inflammatory pathways203,209.
with the Pro12Ala variation in PPARG111. Furthermore,
confirmatory evidence for a genotype–nutrient inter-
action between fibre intake and the rs1800588 poly­
morphism of the gene that encodes hepatic lipase, LIPC,
have been reported112. In addition, another study revealed
an association between a genetic predisposition score
computed by 32 BMI-​related loci and body fat mass,
whereby the risk of an increased BMI was associated with
an increased intake of sugar-​sweetened beverages and
increased genetic risk113. By contrast, one study reported
an interaction between AMY1 (which encodes amylase),
copy number and starch intake114, which is opposed to
previous findings, and investigators have reported that
a reduced number of copies is associated with increased
BMI115. These results highlight the importance of assess-
ing carbohydrate quality and quantity, especially in indi-
viduals who are genetically predisposed to obesity for
whom the type of carbohydrate being consumed could
exacerbate the obesity risk100.
Different investigations have reported an association
between total fat proportion and genes related to food
intake regulation, such as FTO116,117, genes related to fat
metabolism, such as APOA5 (refs118,119), and genes asso-
ciated with adipocyte differentiation, such as PPARG120,
in different populations. The individuals who have risk
alleles for FTO who also consume an elevated proportion
of energy as fat showed an exacerbated increase in obesity
risk compared with those without the risk alleles107,116,117.
Conversely, C carriers of the variant rs662799 in APOA5
who consumed more fat in their diet were protected
from obesity118,119. Furthermore, research that analysed
three case–control studies found a modulatory effect of
Nature Reviews | Endocrinology
Reviews
the gene variant rs1801282 in PPARG. Specifically, in
homozygous individuals (Pro/Pro) there was a direct
association between fat intake and BMI; meanwhile,
individuals who were 12Ala carriers exhibited no asso-
ciation between BMI and fat intake120. In addition, this
study also found an inverse association between mono-
unsaturated fat intake and BMI, highlighting the impor-
tance of the fat profile and not only the total amount of
fat, and the differences in the effects depending on the
genetic background120. These outcomes were confirmed
by subsequent studies carried out in a Mediterranean
population, where this inverse correlation with fat
oxidation after fat load was also reported121,122.
In line with these results, other studies have reported
that abdominal adiposity becomes aggravated in
individuals with the risk alleles for the FTO variant
rs9939609 who have a high saturated fat intake (and
low polyunsaturated fatty acid to saturated fatty acid
ratio), especially in those who already have the metabolic
syndrome123. Additional findings further support the
importance of dietary saturated fatty acid on obesity risk,
where the presence of risk alleles for APOA2 increase the
risk of obesity in the presence of an elevated saturated
fatty acid intake by modulating pathways involved in
branched-​chain amino acids and tryptophan metabo-
lism124,125. Moreover, some authors have reported inter-
actions between fat intake and genetic background based
on a genetic profile risk score on obesity. Specifically,
the authors found variations in obesity risk when indi-
viduals with high and low total saturated fat intake
were compared126, which confirms previous research127.
These studies suggest that dietary fat and the associated
nutritional profile interacts with genes and pathways
related to fat metabolism due to their energetic density
and their role in the palatability of foods. Furthermore,
genes that are potentially associated with regulation of
satiety modulate the influence of fat intake on obesity
development126,127, but this area needs further research.
Gene–protein intake interactions for obesity traits
have been reported by several investigators. For exam-
ple, a large-​scale analysis with multiple populations from
40 studies found a statistically significant association
between the FTO obesity-​related variant and increased
protein intake; the risk of obesity was increased in indi-
viduals with the risk alleles128. The authors suggested a
putative link between the presence of obesity risk alleles in
FTO and protein intake for adipose accumulation128.
In other studies, CTSS, which is associated with fat
body mass129 and protein levels in blood130, was found to
interact with the proportion of protein intake, whereby
a regression analysis showed that people with the risk
allele who had a high intake of protein were at risk of
weight gain131. Meanwhile, in a cohort of individuals
from East Asia, FTO risk allele carriers presented with
increased BMI and waist circumference when they con-
sumed a diet with lower protein intake132. Nonetheless,
some authors have highlighted the importance of the
protein sources in the association with obesity risk and
genetic make-​up. For instance, one group showed dif-
ferent interactions with total protein, animal protein
and vegetable protein when the authors compared indi-
viduals with high and low genetic risk score values for
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obesity103. Therefore, protein and specific amino acids
interact with regard to body weight regulation, where
the genetic background could explain the different
inter-​individual outcomes related to adiposity133.
Genetic information could help to determine the
most appropriate dietary intervention for the prevention
and treatment of obesity, as well as the development of
comorbidities100. Further research should be conducted
to obtain more information on gene–nutrient interac-
tions and on the interconnections (epistasis) presented
in a different cluster of the population. Knowledge from
this research could then be integrated into clinical prac-
tice and inform prescriptions where different macro­
nutrient distributions could be administered depending
on the individual genetic make-​up134–136. In addition,
there has been an increase in research investigating the
effect of macronutrient distribution, calorie restriction
or the intake of specific foods on specific epigenetic
markers, and how they modify metabolic pathways that
are related to macronutrient metabolism or to the risk
of obesity137–139.
Effect of gut microbiota on obesity
Throughout life the gut microbiota is affected by the type
of birth (vaginal or caesarean section), perinatal and
early life feeding, antibiotic use140 and dietary intake141
(Table 2) , which supports a ‘personalized’ medicine
app­roach for every individual, as is the case with genetics.
These factors act by modulating the composition of the
bacterial population that colonizes the intestinal tract142.
At the same time, the gut microbiota has been described
by some authors as an additional environmental feature,
which is intimate with the host metabolism143. Despite
this evidence, the role of the gut microbiome in obe-
sity is still a fairly novel concept and further research
is needed to identify a role for the gut microbiome in
the development of obesity and in treatment strategies.
Box 3 | Protein metabolism
The main function of proteins (which are nitrogenous macronutrients) is structural, but
they are also responsible for enzymatic functions and have endocrine regulatory roles97.
Dietary protein and protein-​derived molecules exhibit orexigenic and anorexigenic
effects that are mediated by different neuropeptides and gut hormones, such as
ghrelin, CCK, GLP1, PYY, leptin, insulin and specific amino acids210. In addition, protein
helps preserve fat-​free mass and skeletal muscle, which promotes the maintenance of
energy expenditure211. In addition, protein has well defined thermogenic properties
that are mediated by oxidative phosphorylation processes, urea synthesis,
gluconeogenesis and energy-​yielding intermediate metabolism pathways96,212.
However, distinctive effects have also been reported for specific proteins, such as
gelatin, in appetite suppression213. Individual amino acids214 might also have specific
roles. For instance, leucine might have a role in mechanistic target of rapamycin–AMPK
signalling, opioid–GABAergic receptor activity and adrenergic and/or noradrenergic
neurons associated with energy balance215. Furthermore, mechanisms related to
protein-​induced satiation have been attributed to calcium-​sensing receptors linked to
amino acids (such as tyrosine, tryptophan or histidine)216, umami substances (including
monosodium glutamate) that affect gastric vagal afferents217 or the aspartame (Asp–Phe)
amino acid derived from sweeteners, which modulates appetite and postprandial
thermogenesis218. For this reason, the evaluation of dietary protein content has been
widely studied quantitatively (by urinary nitrogen, ketogenic state or amino acids in
plasma) and qualitatively (by biological value of proteins, essential amino acids or
vegetable and/or animal protein) to better understand its potential involvement
in energy homeostasis36.
The gut microbiome seems to reflect the lifestyle of the
person; however, whether changes to it are a cause or a
consequence of obesity needs deeper study. Interestingly,
carbohydrates (that is, fibre), protein and lipid intake
affect faecal microorganisms, whereby macronutrients
interact with the microbiota144. Despite these data, the
composition of an individual’s microbiota is unique and
is a representative feature of an individual’s metabolic
and body weight status144,145.
Pioneering studies have described associations
between microbiota populations with the presence of
obesity. Specifically, data show an increase in Firmicutes
and a decrease in Bacteroidetes in obese mice, which
suggests a putative effect of these microorganisms on
host metabolism146. These results were subsequently
confirmed in human studies in which investigators
compared samples from individuals who were lean or
had obesity145.
Some authors have described an increase in the
amount of energy gained from food in individuals with
obesity and have identified increases in Prevotellaceae
and Archaea in stool samples from these individuals147.
Furthermore, bacterial richness and variety has been
inversely associated with adiposity, whereby individ-
uals with a low bacterial richness have elevated adi-
posity, insulin resistance and dyslipidaemia, as well as
low-​grade systemic inflammation144. Other reports also
revealed the effects of gut bacteria, such as Akkermansia
muciniphila, in the modulation of the endocannabinoid
system, and in body weight and food intake regulation148.
The gut microbiota characteristics of individuals with
obesity, however, have shown a wide variability, which
is modulated by several factors including macronutrient
dietary intake. For example, sex-​specific differences in
gut microbiota populations that are associated with obe-
sity were reported in a human study149. In addition, other
researchers have suggested that the differences in the
populations of gut microbiota depend on genetic varia-
tions150. The proportions of bacterial populations, how-
ever, have been shown to be mainly modulated by the
nutritional composition (Table 2) of the diet151. With this
in mind, the identification of individual clusters of bac-
terial populations (named enterotypes) and their asso-
ciations with health and disease suggests an important
role for their use in clinical routines. By studying these
characteristics, investigators could better understand the
different roles of sugar and fibres (as well as fatty acids
and proteins) in eubiosis and dysbiosis, and how these
roles affect patient outcomes and the functionalities of
the microbiota152.
The differences in energy harvesting seem to be
caused by the bacterial production of short-​chain fatty
acids, which improves energy utilization of digestion dis-
cards (the remains of habitual digestion)153. Likewise, the
effects of short-​chain fatty acids on the host have been
associated with energy expenditure via the regulation of
the expression of genes related to thermogenesis, such
as PPARG or UCP2, and with an increase in lipid oxi-
dation154. In addition, short-​chain fatty acids also affect
the modulation of short-​term pathways that are linked to
appetite and food intake in people who are overweight;
the colonic infusion of a short-​chain fatty acid mixture
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Table 1 | Associations between genetic background, macronutrient intake and obesity traits
dietary genes Population characteristics n reported outcome and/or traits ref.
components relationship
Energy
Energy FTO, LEP and LEPR Men in the overweight BMI category 40 + Appetite or feeling of fullness 105

Energy MC4R US women 5,724 + Body weight 108

Energy FTO and MC4R Heterogeneous Review None Weight maintenance 109

(39 articles) reported

Energy FTO US adult twins 114 + Feeling of fullness 106

Total fat FTO From 56 studies 213,173 – Obesity risk 107

Carbohydrates
Carbohydrates ADBR2 Spanish 313 + BMI 110

Carbohydrates PPARG Spanish 313 + Obesity risk 111

Fibre LIPC European women with obesity 549 – Obesity risk 112

Fibre GRS (16 SNPs) Spanish adults 711 – Adiposity markers 103

Starch AMY1 (CNV) Swedish population 4,800 – BMI 114

SSB GRS (32 SNPs) US population >32,000 + BMI 113

Fat
Total fat FTO Saudi Arabian individuals 240 + Early onset of obesity 116

Total fat FTO Spanish adolescents 652 + Adiposity 117

Total fat APOA5 US adults 2,280 – BMI 118

Total fat APOA5 Mediterranean adults 1,465 + BMI 119

Total fat PPARG Three case–control studies 2,141 + Obesity risk 120

Total fat and SFA GRS (63 SNPs) Two US studies 2,818 + BMI 127

Total fat and SFA GRS (95 SNPs) White European adults 48,170 – BMI and waist circumference 126

SFA FTO French adults 1,754 + BMI and waist circumference 123

SFA APOA2 European and Asian individuals 4,602 + BMI 125

MUFA PPARG Spanish men and women 60 – BMI and fat oxidation 121

MUFA PPARG Mediterranean population 1,465 – BMI and body fat 122

Protein
Protein FTO 9939609 Heterogeneous 177,330 + BMI 128

Protein CTSS (3 SNPs) European adults 11,091 + Obesity risk 131

Protein (animal FTO Adolescents of several ethnicities 1,491 Ethnic BMI, waist circumference and 132

and/or plant) differences food intake

Vegetable protein GRS (16 SNPs) Spanish adults 711 – Adiposity markers 103

+, positive association between the SNP (or SNPs); –, negative association between the SNP (or SNPs); CNV, copy number variation; MUFA , monounsaturated fatty
acid; SFA , saturated fatty acid; SNP, single-​nucleotide polymorphism; SSB, sugar-​sweetened beverage.

increased plasma levels of PYY, which is triggered by
the activation of epithelial G-​protein-​coupled recep-
tors (GPR41 and GPR43)155. However, the association
between short-​chain fatty acid richness and bacte-
rial abundance in faeces remains unclear156,157. Future
human intervention studies should help determine the
long-​term benefits for the control of body weight and
adiposity that depend on microbiota fermentation
and energy utilization.
The effect of metabolites that result from the fer-
mentation of dietary macronutrients on obesity and
accompanying comorbidities have been widely inves-
tigated158. Furthermore, carbohydrate intake has been
described as the principal element in the modulation
of the gut microbiota159,160. Fibre acts by modulating
the gastrointestinal transit, glucose absorption and fae-
cal bulking, which affects the glycaemic response and
satiety signals161,162. In addition, fermentable dietary
fibre has a key function in the regulation of microbial
intestinal populations158. The effect of prebiotics, such
as fructo-​oligosaccharides, on gut microbiota has been
proven by several studies, as fructo-​oligosaccharides
modulate the abundance of Faecalibacterium prausnitzii,
among other bacteria, and correlate with the produc-
tion of butyrate, which contributes to the reduction of
food intake through the decrease of neuropeptide Y
expression in the hypothalamus163.
Studies have also investigated the effect of the ‘west-
ern’ diet, which is rich in sugar and artificial sweeten-
ers7, on gut microbiota composition. Unfortunately, the

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association between sweeteners and gut microbiota in with increased expression of mouse genes related to
human obesity remains poorly understood. One such fructose and mannose metabolism, glycolysis and glu-
study, which was carried out in mice, demonstrated that coneogenesis164. An observational study in humans
a western dietary pattern was preferred by Firmicutes, demonstrated the presence of small intestinal bacterial

Table 2 | Associations between macronutrient intake, gut microbiota and obesity in humans
dietary Effect on gut microbiota Associationa outcome and/or rationale Putative metabolic ref.
substrate functionalities mechanisms
concerning obesity
(host metabolism)
Energy
Total energy ↑ Firmicutes to + Increased energy harvest Greater fractional Efficiency of nutrient 185

intake Bacteroidetes ratio of ≈150 kcal, overfeeding decrease in stool absorption

in lean individuals energy loss
Caloric ↑ Akkermansia muciniphila, + Healthier fasting plasma A. muciniphila SCFAs presented an 186

restriction ↑ gene richness levels of glucose, plasma produces SCFAs (such anorectic effect and
levels of triglycerides as acetate) displayed greater
and body fat distribution improvement in insulin
sensitivity and other
clinical parameters
Carbohydrates
Total ↓ Roseburia spp., + Reduction in faecal Association of Butyrate-​induced 160

carbohydrates Eubacterium rectale butyrate supply to the butyrate-​producing suppression of

and Bifidobacteria with
carbohydrate reduction
Fibre ↑ Diversity,
colonic mucosa, which
affected gut health
+ Long weight
bacteria with the orexigenic neuron
faecal butyrate activity that expresses
neuropeptide Y in the
hypothalamus
The fermentation Appetite reduction by 187

↓ Bacteroidetes, ↑ Firmicutes maintenance with of fermentable PYY and GLP1; energy

(Ruminococcaceae and
Lachnospiraceae)
Fibre ↑ Gemmiger, Dorea,
reduced weight gain
independently of energy
intake
+ Differences in gut
carbohydrates yields expenditure increase
the increase of SCFAs by thermogenesis
through the expression
of the genes encoding
PPARγ and UCP1
Microbiota from lean Butyrate products 188

(arabinogalactan Roseburia, Alistipes,
and inulin) Lactobacillus and
Bifidobacterium
(lean participants),
↑ Bifidobacterium
adolescentis, Bifidobacterium
and Faecalibacterium
prausnitzii (lean participants
and those with obesity)
Prebiotics ↑ Bifidobacterium spp.,
microbiota and
metabolites between
lean individuals and
those with obesity
+ Body weight z-​score,
individuals presents can reduce levels of
more n-​butyrate from neuropeptide Y in the
the fermentation of hypothalamus
both substrates than
the microbiota from
those with obesity
NA NA 189

(inulin) ↓ Bacteroides vulgatus body fat and truncal fat

Fat
Total fat and SFA ↑ Bacteroidetes and +/– BMI and enterotypes Firmicutes and Promotion of 172

Actinobacteria, ↓ Firmicutes remained stable during Actinobacteria are pro-​inflammatory

and Proteobacteria 10 days of intervention associated with pathways associated
obesity-​enriched with obesity
genes and reduced
functional diversity
Unsaturated ↑ Bifidobacterium longum + Higher B. longum Unsaturated fats affect Promotion of 190

fatty acids abundance in lean the cell membrane membrane integrity

participants, possible fluidity, regulate and pro-​inflammatory
interaction with fibre neurotransmitter pathways associated
function and reduce with obesity
cytokine production
Protein
Total protein ↓ Total bacteria, ↓ Roseburia – Increase of Increase in isovalerate The pH increase might 169

and/or E. rectale and branched-​chain fatty and isobutyrate induce the reduction
Bacteroidetes acids, pH, phenylacetic concentrations reflect of butyrate-​producing
acid and N-​nitroso the increase in amino bacteria
compounds in faeces acid (valine and
leucine) fermentation
↑, increase; ↓, decrease; NA , not available; SCFA , short-​chain fatty acid; SFA , saturated fatty acid. aAssociation between nutrient and/or dietary substrate and
gut microbiota.

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growth in people with obesity who also had a diet
that was rich in carbohydrates and refined sugar and
deficient in fibre165.
Dietary protein and the modulatory effects of carbo­
hydrates on the gut microbiota166 alter the derivatives
of protein digestion. These derivatives affect energy
metabolism by altering fermentation of aromatic and
branched-​chain amino acids and by acting as precursors
of short-​chain fatty acids167. For instance, the gut bacteria
can shift the source of fermentation when dietary carbo­
hydrate levels in the gut are low168. This situation pro-
motes the catabolism of proteins for fermentation, which
alters intestinal pH, transit times (time between the
entry of the food bulk into the bowel until excretion) and
microbiota communities168. In this context, a trial that
included individuals with obesity showed that following
a diet that was rich in protein resulted in a reduction in
the concentration of short-​chain fatty acids in the gut and
in the abundance of Roseburia and Eubacterium rectale,
together with an increase in branched-​chain amino
acids, phenylacetic acid and N-​nitroso compounds,
which might have deleterious effects on host health169.
By contrast, a review highlighted the anti-​inflammatory
effects of specific amino acids, which enhance gut bar-
rier function through tryptophan gut microbiota metab-
olites170. In addition, the authors of this review reported
a GLP1 modulatory effect on host metabolism and per-
ception of satiety caused by indole, which is a bacterial
metabolite of tryptophan170.
Furthermore, other investigators have suggested
that the involvement of dietary fat intake on weight gain
is caused by other effects aside from the positive fuel
balance171. Diets that are rich in fat could affect the gut
microbiota through an antimicrobial activity, which
promotes the development of dysbiosis associated with
the systemic pro-​inflammatory status related to obe-
sity171. Cross-​sectional research in healthy individuals
found a positive association between Bacteroidetes and
Actinobacteria with fat intake in the habitual diet172. In
addition, this research revealed that the existing taxa
associated with BMI were also correlated with calorie
intake from saturated fatty acids172. Another study that
investigated the quality of fat intake in monozygotic
twin pairs found a positive association of monounsatu-
rated fatty acids with an abundance of Bifidobacterium
and Bacteroidetes and between n-3 polyunsaturated
fatty acids and Lactobacillus, while the association was
inverse between n-6 polyunsaturated fatty acids and
Bifidobacterium173. Nevertheless, some authors sug-
gested that the inclusion of probiotics in the diet could
mitigate the detrimental effect of dietary fats on weight
maintenance and fat accumulation174,175.
Integrative studies in obesity
Precision nutrition and precision medicine are becom-
ing important issues with regard to body weight mainte-
nance and obesity management. Personalization in these
instances is not only based on the metabolic phenotype,
food preferences, clinical history or lifestyle patterns, but is
rooted in the emerging criteria of individualization, where
genotype and the composition of gut microbiota are the
basis for tailor-​made disease treatment, particularly for
Nature Reviews | Endocrinology
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metabolic disturbances. As a result, more researchers
are becoming interested in dietary patterns to investi-
gate the role of the complex interactions between food
nutrients, gut microbiota composition and the genetic
background176. A controlled-​feeding trial that included a
cohort of healthy people who were eating a high fat–low
fibre diet or a low fat–high fibre diet found changes in
gut microbiota composition after 24 h of dietary interven-
tion and these changes remained stable during 10 days
of study172. The investigators also reported associations
between long-​term dietary pattern and bacterial popu-
lations. More specifically, they reported a relationship
between Bacteroidetes with protein and animal fat and
Prevotella with carbohydrates172. Similarly, other nutri-
tional interventions found a decrease in bacterial diversity
after a high fat–high sugar and low fat–high sugar diet in
rats. These diets were associated with an increase in intes-
tinal inflammation and shifts in vagal gut–brain links that
relate to incremental body fat deposition177.
Some authors have highlighted the promise of using
an integrative analysis of gut microbial populations,
together with metabolomics analyses, to objectively
evaluate the adherence to healthier dietary patterns and
to help clarify the explicit dietary components of these
patterns, such as the Mediterranean dietary pattern, and
their putative role in the complex interactions regard-
ing the development of cardiometabolic disorders178.
For instance, a trial has reported differences in gut
microbiota composition associated with a healthier diet­
ary profile in people with obesity179. More specifically,
individuals who had a healthier dietary intake had ele-
vated microbial richness and reduced concentrations of
inflammatory markers179. Similarly, some authors high-
lighted the need for further investigation to determine
the bacterial response to specific dietary interventions
and the beneficial effects on the host metabolism180,181.
However, novel metabolic markers or new technologies
that can help clarify the nutritional intake of specific
diets are needed to develop more specific nutritional
assessments and determine how they affect gut micro-
biota and genetic interactions. Such technologies would
allow a more accurate determination of the specific effect
of macronutrients on metabolic pathways and endocrine
signals that are related to the development of obesity.
Indeed, some research has confirmed previous associ-
ations between the host genotype and gut microbiota
in relation to visceral adiposity39,182. More specifically,
one group described the beneficial effect of a low-​calorie
diet high in protein on individuals in the overweight
BMI category who had a Bifidobacterium-​related LCT
genotype variation (LCT encodes lactase)150.
Further to these studies, data suggest that interac-
tions between dietary factors, such as macronutrient
distribution, gut microbiota composition and genetic
background, are associated with the metabolic impair-
ments found in obesity25. The holistic study of individual
features and the associated sensibility to gut micro­
biota metabolites could help to develop new strategies in
nutritional assessment that improve the efficacy of the
prevention and treatment of obesity183. Further research
on this topic should be designed to determine screen-
ing and detection tools that rely on specific enterotypes,
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Exposome
Encompasses life-​course
environmental exposures
(including lifestyle factors) from
the prenatal period onwards,
including the body’s response
through different endogenous
metabolic processes.
metabolites in human health, energy balance and weight
control158 to enhance the personalization of clinical prac-
tice for the prevention and the treatment of obesity184.
With the final aim of studies being the development of
sound precision nutrition counselling, further research
needs to be undertaken to better understand the complex
interactions involved in the development of obesity. This
research needs to be conducted before the integration of
all the individual information on lifestyles and environ-
ment, cultural cues, clinical history (including adverse
effects of drugs, allergies and intolerances), level of phys-
ical activity, sleep and dietary patterns, food preferences
and behavioural factors (that is, the exposome) with
biological data including circadian rhythms, genetics,
epigenetics, metagenomics and metabolomics.
Conclusion
Macronutrient intake distribution and dietary compo-
sition are becoming important areas of research with
regard to understanding body fat deposition and weight
stability. Scientific advances are showing that to com-
bat the obesity epidemic scientists need to consider the
specific contribution of not only carbohydrates, pro-
teins and lipids, but also individual amino acids, fatty
acids and diverse carbohydrate-​derived molecules, as
well as the interactions they have with genetic make-​up
and the gut microbiota composition — which is the basis
for precision nutrition and medicine.
Fat and sugar intake, as energy yielding macronutri-
ents, have been considered the main drivers of the obe-
sity epidemic as both contribute to the energy supply.
However, because they share common metabolic path-
ways related to energy homeostasis51, it is challenging
to delineate from the available evidence the individual
contribution of each macronutrient to obesity. This
issue is compounded further due to the complex inter-
actions with regard to fuel metabolism and because
the integrative metabolic flexibility of each individual
enables people to adapt energy utilization from different
sources depending on availability and needs62. In other
words, it is difficult to ascribe a more deleterious role
for fat compared with sugars as the whole energy intake
compared with expenditure could be more important
than the specific sources of energy concerning weight
gain. However, the role of specific fatty acids and sugars
might explain some differences in energy efficiency,
while protein seems to reduce appetite and promote
thermogenesis with a positive effect on body weight
maintenance56.
Excessive body weight and adipose tissue accu-
mulation depend on energy balance, where chronic
energy-​yielding macronutrient intake is higher than
energy expenditure, which is under neuroendocrine reg-
ulation. Intricate fuel metabolism interactions involving
carbohydrate, lipid and protein utilization complicate
the interpretation of the specific contributions from
such macronutrients to energy requirements and the
demands of cells. Furthermore, the energy equilibrium
is sustained by complex and inter-​related regulatory
processes that implicate appetite and/or satiety con-
trol mediated by neuroendocrine signals, in addition
to intermediate metabolic pathways that affect carbo-
hydrate (glucose) utilization, lipid turnover (lipogene­
sis and lipolysis), protein-​driven thermogenesis and
adipocyte physiology.
The frequent consumption of some simple sug-
ars, such as glucose and fructose, as well as the intake
of saturated fat and some specific fatty acids, seem to
be the main contributors to the growing prevalence of
obesity1. The satiating properties of dietary fibre and
satiety-​promoting properties of dietary protein help with
body weight maintenance and energy intake control in
long-​term interventions. These positive interactions are
probably induced by fat-​free mass and resting energy
expenditure preservation, but evidence from the past
10 years suggests that specific fatty acids and amino
acids might be involved in the obesogenic state, where
some polymorphisms in FTO and other genes might
be involved100. However, there is no general consensus
on whether there is a macronutrient interaction with
this FTO variant109, which therefore warrants further
investigation.
Overall, current evidence suggests that energy surplus
is the main driver of overweight and obesity, where the
idea that refined sugars and some fats have complemen-
tary roles in weight gain is still a matter of controversy
if calories from different macronutrients count as equal.
Personal features associated with the genetic make-​up
and gut microbiota could explain some inter-​individual
differences to dietary macronutrient intake that affects
body weight-​for-​height and fat mass150. Indeed, further
integrative investigations are needed to understand the
mechanisms that underlie individualized macronutrient
metabolic networks for energy thermodynamics and to
devise dietary strategies based on the individual’s own
precision nutrition criteria.
Published online xx xx xxxx

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Acknowledgements
R.S.-​C. acknowledges financial support from the Juan de la
Cierva Programme — Training Grants of the Spanish State
Research Agency of the Spanish Ministerio de Ciencia e
Innovación y Ministerio de Universidades (FJC2018-
038168-​I). R.S.-​C., S.N.-​C. and J.A.M. were part of the EU
project Food4Me supported by the European Commission
under the Food, Agriculture, Fisheries and Biotechnology
Theme of the 7th Framework Programme for Research and
Technological Development (ID no. 265494). M.A.M.-​G.
acknowledges the support of the European Research Council,
Advanced Research Grant, PREDIMED-​PLUS (ERC-2013-​ADG
#340918).
Author contributions
All authors contributed to all aspects of the manuscript.
Competing interests
The authors declare no competing interests.
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Supplementary information
Supplementary information is available for this paper at
https://doi.org/10.1038/s41574-020-0346-8.
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