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Metabolism in Obesity 19
Jose E. Galgani, Víctor Cortés, and Fernando Carrasco
All forms of life require exogenous energy supply 2 Role of Energy Homeostasis
and the biochemical machinery for transforming Regulation on Obesity
fuels to usable forms of cellular energy. This Pathogenesis
energy is required to sustain multiple processes
that are pivotal for survival of living organisms, The maintenance of stable body mass and com-
including the maintenance of electrochemical gra- position requires that cumulative energy intake
dients, macromolecule synthesis and breakdown, over a long period of time (days to weeks)
and thermogenesis, among many others (Rolfe matches cumulative energy demand, resulting in
and Brown 1997). Energy resides in the carbon- null energy balance. Upon these conditions, net
hydrogen bonds of carbohydrate, fat, and protein macronutrient storage is also null, and thus,
and only can be used by cells after being trans- whole-body mass and composition are constant.
ferred to suitable energy carriers. In the mitochon- Therefore, null energy balance necessarily derives
dria, a sequence of complex reactions removes from that the average proportion of macronutrient
hydrogen atoms (i.e., dehydrogenation) from oxidized (respiratory quotient, RQ) equals the
energy substrates. The energy contained in the proportion of dietary macronutrients available
resulting transmembrane proton (H+) gradient is for oxidation (food quotient, FQ) over a period
ultimately transferred to cellular energy carrier (Hill et al. 1991; Westerterp 1993).
molecules (i.e., phosphorylated adenosine Nonetheless, long-term energy flux stability is
nucleosides). the integrated result of the intra- and inter-day
Thermodynamically, obesity pathogenesis fluctuations in both energy/macronutrient intake
requires a chronic positive energy balance in and energy expenditure that lead to either slightly
19 Carbohydrate, Fat, and Protein Metabolism in Obesity 329
well as in adipocytes and is largely responsible for important contributor to the decreased whole-
insulin-stimulated glucose uptake in those cells. body glucose uptake in obese patients was the
In addition, GLUT4 translocation from the cyto- diminished insulin-stimulated glucose clearance
sol to the plasma membrane is also stimulated by by skeletal muscle. At the molecular level,
muscle contraction, and this seems to be driven by insulin-stimulated GLUT4 translocation is quan-
a decrease in cellular oxygen concentration (Egan titatively lower in insulin-resistant obese individ-
and Zierath 2013). uals versus their normal counterparts, which is
To prevent the outflow of newly incorporated consistent with the impaired insulin-stimulated
glucose, this sugar is rapidly phosphorylated. This glucose transport detected in muscle biopsies of
is an ATP-dependent reaction catalyzed by hexo- obese versus lean subjects (Dohm et al. 1988;
kinases. The isoform found in the liver (type Goodyear et al. 1995).
4 hexokinase, glucokinase) has relatively low In response to a dietary challenge (i.e., inges-
affinity for glucose, with a Km that doubles the tion of a fixed glucose dose or a mixed meal) and
fasting blood glucose concentration (~5 mM). in contrast to the glucose clamp method, on which
This kinetic feature allows hepatocytes to phos- a fixed insulin dose is infused and the adminis-
phorylate glucose that massively comes from tered glucose is continuously adjusted so
intestine after meals. Once glucose is converted euglycemia is maintained, whole-body glucose
to glucose-6-phosphate (G6P), it has two major uptake mostly depends on the capacity of pancre-
metabolic fates: (i) glycolytic oxidation to pyru- atic beta (β) cells to release as much insulin as
vate and further conversion to lactate (anaerobic required to compensate any eventual defect on
condition) or oxidation to acetyl-CoA (aerobic insulin action in tissues. Thus, in obese individ-
condition) and (ii) conversion to glucose-1-phos- uals with normal beta (β)-cell function,
phate (G1P), the precursor of glycogen synthesis. hyperinsulinemia might well be sufficient to com-
Under non-insulin-stimulated conditions (e.g., pensate the defect in peripheral insulin action and
overnight fasting), circulating glucose is mostly maintain normal glucose uptake (Fig. 1). How-
taken up by nonskeletal muscle tissues (e.g., cen- ever, contrary to this prediction, (Baron
tral nervous system), with about 20 % being et al. 1990) found that both whole-body and skel-
cleared up by the skeletal muscle (Baron etal muscle glucose uptake were both reduced
et al. 1988). Interestingly, both lean and obese after an oral glucose dose (1 g per kg body weight)
individuals have similar glucose clearance rates in obese when compared with lean individuals
(Kelley et al. 1999a), which is consistent with the (Laakso et al. 1990).
observation that most of the glucose uptake in
fasting conditions relies on insulin-independent
mechanisms. Concordantly, the transport of a 3.3 Glycolysis and Oxidation
non-metabolizable glucose analog (3-O-
methylglucose) (Dohm et al. 1988) and the con- The glycolytic processing of one mole of G6P
tent of G6P (Allenberg et al. 1988) were similar in yields two moles of pyruvate and two moles of
muscle biopsies from lean and obese donors. ATP (net production). In turn, pyruvate can be
Under insulin-stimulated conditions, converted to lactate through the action of lactate
Bonadonna et al. compared glucose uptake at dehydrogenase or oxidized to acetyl-CoA through
different insulin doses (4–400 mUm 2min 1) the action of the mitochondrial pyruvate dehydro-
in lean and obese volunteers by the glucose genase complex (PDH). In the mitochondria,
clamp procedure (Bonadonna et al. 1990). They acetyl-CoA is integrated in the tricarboxylic acid
found that insulin dose-response curve was right (TCA) cycle, and its oxidation results in the
shifted in obese when compared with lean indi- release of CO2 and the generation of reducing
viduals indicating impaired insulin action. Laakso equivalents (NADH and FADH2). The energy
et al. (Laakso et al. 1990) reported that the most contained in these molecules is used to build an
332 J.E. Galgani et al.
Insulin Insulin
Glucose Glucose
CO2 CO2
Insulin Insulin
Glucose Glucose
CO2 CO2
Fig. 1 The figure represents glucose uptake in lean, insulin concentration eventually compensates any defec-
insulin-sensitive and obese, insulin-resistant individuals tive tissue insulin action, which might even prevent the
under two insulin-stimulated conditions: glucose clamp decrease in glucose uptake and further glucose oxidation.
(supraphysiological) and postprandial (physiological). In Thus, during the glucose clamp condition, insulin resis-
the glucose clamp, insulin-stimulated glucose uptake is by tance is manifested by decreased glucose uptake and oxi-
definition impaired in insulin-resistant versus insulin- dation at a similar circulating glucose and insulin
sensitive subjects. This leads to diminished intracellular concentration. In turn, in the postprandial condition, insu-
glucose utilization and glucose oxidation (CO2 produc- lin resistance is mainly characterized by hyperinsulinemia
tion). Instead, in the postprandial condition, circulating with eventually normal glucose utilization
H+ gradient across the internal membrane of the a respiratory chamber for 48 h, was similar in
mitochondria and ultimately drive mitochondrial obese and lean subjects (Weyer et al. 2001).
ATP synthesis. Regarding postprandial conditions, we
There is a plethora of studies aimed to assess assessed whole-body glycolysis and glucose oxi-
whole-body and skeletal muscle glucose oxida- dation rates in insulin-sensitive and insulin-
tion as well as the ratio between glucose-to-fat resistant individuals, defined by the glucose
oxidation in obese patients in comparison with clamp technique (Galgani and Ravussin 2012).
lean individuals (Galgani et al. 2008b). Most of In this study, the insulin-resistant group also
these studies have been conducted in fasted indi- resulted to be heavier than the insulin-sensitive
viduals, which is hardly distinguishable whether group (29 4 [SD] vs. 25 4 kgm 2, respec-
the reported differences among obese and lean tively). Despite these contrasting characteristics,
subjects correspond to intrinsic metabolic alter- whole-body glycolysis and glucose oxidation
ations of obesity or are merely result from inaccu- over 4 h of ingesting a standard oral glucose
rate control of previous dietary and metabolic dose were similar between groups. In line with
conditions. Interestingly, when macronutrient this finding, no differences in the oxidative dis-
intake and energy balance were carefully con- posal of glucose and other macronutrients in
trolled, fasting respiratory quotient, measured in obese compared to lean subjects were observed
19 Carbohydrate, Fat, and Protein Metabolism in Obesity 333
over an 8-h feeding protocol (Owen et al. 1992). Another aspect deserving further analysis is the
Using a more prolonged feeding paradigm (96 h), observation that obese vs. lean individuals show
McDevitt et al. (McDevitt et al. 2000) delivered a relatively elevated blood lactate levels (Lovejoy
hypercaloric diet (50 % excess energy over indi- et al. 1990, 1992). In fact, obesity and insulin
viduals’ energy requirements) to lean and obese resistance are both independently associated
volunteers and monitor them in a whole-body with increased lactacidemia (Galgani et al. 2013;
metabolic chamber. Interestingly, both groups Adeva-Andany et al. 2014). Furthermore, direct
showed a similar capacity to handle energy assessment of lactate turnover showed increased
excess, with macronutrient oxidative disposal conversion of lactate to glucose and from glucose
remaining similar between groups. to lactate in obese vs. lean children (Stunff and
Whole-body glucose oxidation has also been Bougneres 1996). The pathophysiological rele-
assessed during euglycemic-hyperinsulinemic vance of this finding and its mechanistic basis
clamp conditions, where the extent at which RQ remain unclear. At the molecular level, the ability
increases upon insulin stimulation is used as a to convert pyruvate to lactate or acetyl-CoA is
marker of metabolic flexibility (Galgani pivotal for cellular metabolic flexibility. In this
et al. 2008b). It has been reported that insulin regard, an animal model having defective PDH
resistance is accompanied by an impaired ability activity (by hyperacetylation of PDH E1 alpha (α)
to increase whole-body and muscle-specific glu- subunit) has impaired metabolic flexibility,
cose oxidation in the clamping, indicating meta- reduced glucose oxidation, enhanced lactate pro-
bolic inflexibility (Kelley et al. 1999b; Galgani duction, and higher fatty acid oxidation even in
et al. 2008a) (Fig. 1). On the other hand, improve- the fed state (Jing et al. 2013). Future studies
ment of insulin sensitivity, for example, after should focus in investigating the molecular basis
weight loss, is paralleled by enhanced metabolic of metabolic inflexibility as well as its pathophys-
flexibility (Kelley et al. 1999a; Galgani iological meaning.
et al. 2008a). Traditionally, these findings have
been considered a feature of intrinsic cellular
defects, mostly at the mitochondrial level, owing 3.4 Glucose Storage
to reduced ability to switch off lipid oxidation and
simultaneously switch on glucose oxidation in the Conversion of G6P to G1P is mediated through
transition from fasting to insulin-stimulated con- phosphoglucomutase. G1P is then converted to
ditions (Muoio 2014). uridine diphosphate (UDP) glucose and finally
An alternative explanation for the impaired bounded to a growing glycogen polymer. Insulin
capacity to raise glucose oxidation over lipid stimulates glycogen synthesis by relieving the
oxidation that insulin-resistant individuals inhibition that glycogen synthase kinase 3 exerts
exhibit in the glucose clamping is that this phe- on glycogen synthase. Also, insulin-mediated
nomenon results from the lower intracellular glu- GLUT4 translocation to plasma membrane results
cose availability of these individuals in in higher glucose flux and thus higher availability
comparison with insulin-sensitive subjects of the substrates for glycogen synthase action
(Galgani et al. 2008a) (Fig. 1). Indeed, when (Yki-Jarvinen et al. 1987). Glycogen is synthe-
insulin-stimulated glucose disposal rate was sized by both the liver and skeletal muscle. The
taken into account, the increase in the RQ former has a higher content per gram of wet tissue,
remained equivalent in obese, nondiabetic whereas the latter has a greater contribution to
vs. obese, type 2 diabetic patients. In addition, total body glycogen because of its larger contri-
similar metabolic flexibility after correcting for bution to the body mass (~50 % of fat-free mass in
insulin-stimulated glucose disposal rate was also adult individuals).
observed when obese, type 2 diabetic patients Hepatic glycogen has a systemic role because
were studied before and after a one-year weight it contributes to sustain hepatic glucose produc-
loss intervention (Galgani et al. 2008a). tion and normoglycemia during periods of fasting.
334 J.E. Galgani et al.
In contrast, skeletal muscle glycogen mostly sus- suppress this process is observed in obese individ-
tains local ATP production during contraction. uals (Bonadonna et al. 1990). Epidemiological
Under conditions of limited exogenous glucose studies have consistently found a direct correlation
supply, glycogen is hydrolyzed in order to between abdominal obesity and insulin resistance
increase G6P supply, which is then converted to and its systemic consequences, the so-called meta-
glucose by action of glucose-6-phosphatase in the bolic syndrome. However, at the tissue level,
liver. G6P cannot be converted to glucose in skel- intrahepatic rather visceral fat associates with
etal muscle because it lacks glucose-6-phospha- impaired hepatic glucose control (Fabbrini
tase, so G6P is metabolized to pyruvate. It has et al. 2009). These findings suggest that the meta-
been reported that obese individuals have bolic dysfunction of the liver, more than any other
decreased glycogen synthase activity under intra-abdominal organ, is central in the pathogene-
fasting conditions, although muscle glycogen sis of insulin resistance. In concordance with this
content remained unaltered (Allenberg hypothesis, the surgical removal of visceral adi-
et al. 1988). pose tissue appeared to have little impact on insulin
Under glucose clamp conditions, non-oxida- sensitivity in humans (Fabbrini et al. 2010; Dunn
tive glucose disposal, mostly dependent on glyco- et al. 2012; Lima et al. 2013). The fact that less than
gen synthesis, is decreased in obese when 20 % of portal vein free fatty acids (FFA) comes
compared with lean individuals (Young from visceral fat in lean and obese humans while
et al. 1988), possibly owed to decreased intracel- ~10 % of the total FFA found in peripheral blood
lular glucose availability and lower insulin-depen- circulation is derived from visceral fat challenges
dent glycogen synthase activity (Cline et al. 1999; any causative role of visceral fat on metabolic
Hojlund et al. 2009). However, under feeding disturbances (Nielsen et al. 2004).
conditions, whole-body non-oxidative glucose
disposal was similar in lean and obese females
studied for 96 h in a whole-body metabolic cham- 3.6 De Novo Lipogenesis
ber (McDevitt et al. 2000).
Although the main metabolic fates of glucose are
oxidation or glycogen synthesis, under special
3.5 Hepatic Glucose Production metabolic circumstances, glucose can also be
converted into palmitate, the main product of
Hepatic cells can produce glucose out of two endogenous fatty acid synthesis pathway. Oxida-
different mechanisms: (i) glycogenolysis, i.e., tion of acetyl-CoA in the mitochondria originates
hydrolysis of stored glycogen, and citrate, a TCA intermediary. Under conditions of
(ii) gluconeogenesis, i.e., de novo glucose produc- excess glucose supply, citrate leaves the mito-
tion out of nonsugar precursors. Conditions of chondria and is converted to acetyl-CoA and oxa-
limited exogenous glucose supply are character- loacetate by the action of citrate lyase in the
ized by low blood insulin-to-glucagon ratio. This cytosol. Acetyl-CoA is then carboxylated to
hormonal milieu promotes glycogenolysis as well malonyl-CoA in a reaction stimulated by insulin
as gluconeogenesis. Biochemically, gluconeogen- and catalyzed by acetyl-CoA carboxylase.
esis follows the reverse glycolytic flux, although Malonyl-CoA is the substrate of fatty acid
some reactions are exclusive for glycolysis (i.e., synthase that generates palmitate in a multistep
glucose phosphorylation and the synthesis of fruc- sequence of NADPH-dependent reactions. There-
tose-6-phosphate and phosphoenolpyruvate). fore, de novo lipogenesis (DNL) only occurs
Thus, gluconeogenesis requires specific energy- when cellular energy status is high (e.g., it
demanding enzymes to convert precursors such as requires of NADPH) and excess glucose is largely
pyruvate, alanine, lactate, and glycerol to glucose. available.
Increased basal (fasting) hepatic glucose pro- Decades ago, it was postulated that DNL was
duction as well as impaired ability of insulin to partially responsible for increased adiposity of
19 Carbohydrate, Fat, and Protein Metabolism in Obesity 335
with some authors proposing that dietary fructose chylomicrons deliver their lipid load mostly to
is intrinsically harmful for humans (Bray and the WAT, skeletal muscle, and heart. Finally, chy-
Popkin 2014), whereas others postulate that lomicron remnants are cleared by the liver. In turn,
energy overconsumption is the major factor lead- hepatocytes incorporate TAG into secreted
ing to metabolic disturbances, regardless of the VLDL, which can then be hydrolyzed by LPL
energy source (Kahn and Sievenpiper 2014). and the released FFA taken up by WAT and
muscle.
LPL is located on the endothelial surface of
4 Fat Metabolism in Obesity WAT capillaries and is potently regulated by insu-
lin. Circulating as well as LPL-released FFA are
4.1 Overview of Fat Metabolism internalized by a number of binding proteins pre-
sent in the plasma membrane of adipocytes,
Fats are integral components of all cellular sys- including the scavenger receptor FAT/CD36 and
tems and fulfill energetic, structural, and regula- members of fatty acid transport protein (FATP)
tory roles. Fatty acids and cholesterol are the most family (Hajri and Abumrad 2002). Importantly,
abundant dietary lipids. Dietary fatty acids are whereas FAT/CD36 is abundant in adipose tissue
mostly found as TAG in WAT, which is able to and skeletal muscle, it is expressed at very low
store a vast amount of energy (~7,000 kcal/kg). levels in the adult liver. Inside the cell, fatty acids
Because of its ability to buffer short- and long- are rapidly esterified with coenzyme A (CoA) by
term fluctuations in calorie intake, WAT is a major the action of acyl-CoA synthetase. Acyl-CoAs are
evolutionary adaptation against starvation in ver- then esterified to glycerol-3-phosphate backbone
tebrates. WAT also secretes a variety of endocrine for glycerolipid and glycerophospholipid synthe-
factors, called adipokines, which integrate whole- sis in a series of reactions catalyzed by
body energy balance, feeding behavior, basal met- acyltransferases and phosphatases. In the muscle
abolic rate, insulin sensitivity, and vascular func- and liver, acyl-CoAs are mainly destined to mito-
tion. WAT also regulates fertility, mating chondrial beta (β)-oxidation for ATP synthesis. In
selection, offspring growth, immune function, the brown adipose tissue, acyl-CoAs are burnt out
and even bone accrual (Norgan 1997; Trujillo for heat generation upon cold and/or adrenergic
and Scherer 2006). stimulation (Ravussin and Galgani 2011). Fatty
Fatty acid oxidation fulfills 25–45 % of daily acids can also be esterified to sphingosine to form
energy needs in humans, which in an average ceramide. Some of these lipids (e.g.,
healthy adult represents about 60–110 g of fat per diacylglycerol, DAG, and ceramide) are well-
day. Unlike fatty acids, cholesterol cannot be oxi- characterized second messengers in signaling
dized for energy production and can only be pathways and have been consistently implicated
converted to derivative sterols, steroids, and biliary in the pathogenesis of insulin resistance (Coen
acids for disposal. Abnormal lipid accumulation in and Goodpaster 2012).
non-adipose tissues, such as blood, muscle, and the In fasted individuals, circulating FFA are the
liver, is a frequent abnormality in obesity, and it is main source for the synthesis of hepatic TAG, and
possibly connected with the insulin resistance pre- they constitute the bulk of fatty acids incorporated
sent in these individuals (McGarry 2002). in TAG of secreted VLDL particles (Parks
Dietary TAG is hydrolyzed in the lumen of et al. 1999). In addition, low insulin-to-counter-
small intestine by pancreatic lipase, and the regulatory hormone ratio triggers intracellular
released fatty acids are absorbed and reesterified lipolysis of TAG in adipocyte lipid droplets.
by enterocytes into TAG. Small intestine incorpo- FFA are released to the extracellular space and
rates this TAG and other lipid nutrients and vita- circulate bound to plasma proteins, mostly albu-
mins in chylomicrons, which ultimately reach min. Then, FFA are taken up in non-adipose tis-
systemic circulation. Upon extracellular hydroly- sues for reesterification, oxidation, or hepatic
sis mediated by lipoprotein lipase (LPL), conversion to ketone bodies.
19 Carbohydrate, Fat, and Protein Metabolism in Obesity 337
which suggests impaired insulin-dependent glu- content and lower circulating glucose, indicative
cose homeostasis (Ibrahimi et al. 1999). of enhanced insulin sensitivity. In turn, etomoxir-
In humans, the assessment of tissue fatty acid treated mice had increased muscle TAG and DAG
uptake has been restricted to skeletal muscle and content in parallel with improved insulin-
adipose tissues. In vitro determinations performed stimulated GLUT4 translocation (Timmers
in giant sarcolemmal vesicles have suggested that et al. 2012). Taken together, these findings suggest
obese and type 2 diabetic patients have increased that reduced fat oxidation does not necessarily
fatty acid uptake as well as increased membrane- impair insulin sensitivity by itself.
associated FAT/CD36 and intramuscular TAG
content (Bonen et al. 2004). However, gene
expression analysis of muscle FATP has showed 4.4 Fatty Acid Turnover
inconsistent results in both lean and obese indi-
viduals (Simoneau et al. 1999; Bonen et al. 2004; Fatty acids are stored as TAG in lipid droplets,
Pelsers et al. 2007). On the other hand, in vivo which are dynamic structures that appear to regu-
studies found similar skeletal muscle fatty acid late intracellular fatty acid trafficking (Walther
uptake rate in fasted and insulin-stimulated lean and Farese 2012). Thus, the signaling cascade
and obese subjects (Kelley et al. 1999a). mediating lipolysis converges in the elevation of
intracellular cAMP and activation of protein
kinase A. This enzyme phosphorylates lipid
4.3 Fatty Acid Oxidation droplet-associated protein perilipin to allow adi-
pose TAG lipase (ATGL, also known as patatin-
Fatty acids are the main metabolic fuel for oxida- like phospholipase domain-containing protein
tion in the transition from fed to fasted condition. 2 and desnutrin) to physically interact with the
Fatty acid oxidation is regulated at three enzyme- lipid droplet surface and hydrolyze TAG in the
mediated steps: (i) fatty acid activation to acyl- sn-1 position (Zimmermann et al. 2004).
CoA in cytosol, (ii) acyl-carnitine translocation to Resulting sn-2,3 DAG is subsequently hydro-
the mitochondrial matrix (catalyzed by carnitine lyzed by hormone-sensitive lipase and monoacyl-
palmitoyltransferase [CPT] 1), and (iii) mito- glycerol lipase (Walther and Farese 2012; Badin
chondrial beta (β)-oxidation through four sequen- et al. 2013).
tial enzymatic reactions. The balance between glycerolipid synthesis
Impaired fatty acid oxidation attributed to and intracellular lipolysis ultimately determines
mitochondrial abnormalities has been postulated tissue lipid balance as well as the synthesis of
as a major driver of muscle and hepatic fat accu- lipid intermediates (Badin et al. 2013). Thus, the
mulation leading to insulin resistance (Kelley and increase in lipolytic rates led to higher fatty acid
Mandarino 2000; Shulman 2014). In line with this availability as well as de novo ceramide synthesis
hypothesis, Kim et al. found reduced palmitate in a muscle cell line overexpressing ATGL (Liu
(CPT1-dependent) and palmitoyl-carnitine et al. 2007). Alternatively, incomplete TAG
(CPT1-independent) oxidation as well as lower hydrolysis might also favor DAG accumulation
CPT1 activity in muscle biopsies from obese ver- (Badin et al. 2011).
sus lean donors (Kim et al. 2000). In vivo human The relevance of fatty acid turnover is
studies have only partially corroborated this find- highlighted by studies showing that whole-body
ing (Galgani et al. 2008b). On the other hand, adiposity associates directly with intramyo-
experimental inhibition of in vivo fatty acid oxi- cellular lipid content, but not with muscle content
dation through administration of etomoxir (a drug of DAG or ceramide (Moro et al. 2009). Thus,
that decreases CPT1 activity) led to expectedly muscle-specific lipid metabolism is a determinant
higher glucose-to-fat oxidation ratio, which was of muscle fatty acid turnover that is independent
accompanied by higher sarcolemmal GLUT4 of total body adiposity level. In this regard, the
19 Carbohydrate, Fat, and Protein Metabolism in Obesity 339
DAG-to-TAG hydrolase activity ratio (an index of sensitivity, further supporting the role of exces-
incomplete TAG hydrolysis) seems to be lower in sive lipid levels in insulin resistance pathogenesis.
obese individuals, which is accompanied by For instance, thiazolidinediones reduce plasma
increased muscle ceramide and DAG content as FFA concentration and liver TAG content while
well as impaired insulin sensitivity (Itani enhancing insulin-stimulated glucose disposal
et al. 2002; Moro et al. 2009). rate in type 2 diabetic subjects (Mayerson
et al. 2002; Promrat et al. 2004). Importantly, the
role of exercise, a well-established insulin-sensi-
4.5 Consequences of Altered Tissue tizing tool, on intramuscular TAG remains con-
Lipid Balance troversial. Some studies have shown that physical
training decreases intramyocellular TAG (Berg-
Obesity is characterized by increased WAT mass at man et al. 1999), whereas others found the oppo-
the subcutaneous and intra-abdominal level. As site result (Hoppeler et al. 1985). What seems to
mentioned above, obese people commonly have be consistent is that the increased intramyocellular
augmented tissue lipid accumulation in the liver, lipid content normally observed in endurance-
skeletal muscle, and heart (Shulman 2014). It trained athletes does not associate with impaired
appears that elevated fat content in ectopic versus muscle insulin sensitivity, and this phenomenon
eutopic (i.e., WAT) location is more deleterious for has been referred as the athlete’s paradox
whole-body and tissue metabolic homeostasis. In (Goodpaster et al. 2001).
fact, clinical and experimental observations suggest Ectopic fat accumulation is also instrumental
that excessive fat accumulation in non-adipose cells to explain why lipodystrophic patients, who have
is causative of insulin resistance in obese individ- severe paucity of adipose tissue mass, show
uals (Krssak et al. 1999; McGarry 2002; Virtue and severe insulin resistance. These individuals are
Vidal-Puig 2008; Moro et al. 2009). Upon this characterized by substantial accumulation of
hypothesis, chronic caloric overload results in a lipids in the liver and skeletal muscle (Gan
series of pathologic changes in the WAT, including et al. 2002; Simha et al. 2003). Remarkably,
exaggerated hypertrophy of adipocytes, activated leptin, the most potent insulin sensitizer for
immune cells infiltration, abnormal vascular sup- patients with generalized lipodystrophy, also
ply, and fibrotic extracellular matrix (Rutkowski decreases lipid overload in the liver and skeletal
et al. 2015). This pathologically remodeled adipose muscle (Oral et al. 2002; Simha et al. 2003).
tissue lacks the ability to fully expand and thus
leaks fatty acids toward cells and tissues that are
not adapted to store massive amounts of these mol- 5 Protein Metabolism in Obesity
ecules (Rutkowski et al. 2015).
In support of this hypothesis, type 2 diabetic 5.1 Overview of Protein
patients have increased intramyocellular TAG Metabolism
content (Anastasiou et al. 2009; Nielsen
et al. 2010) as well as postprandial hepatic and Proteins are heterogeneous macromolecules with
skeletal muscle fat storage (Ravikumar a broad range of molecular mass, structure, and
et al. 2005). These findings are in line with the functions. All the biological properties of proteins
observation that intrahepatic fat correlates with are determined by their unique sequence of amino
impaired glucose tolerance, systemic insulin resis- acids. Amino acids are organic structures
tance, and increased circulating levels of enlarged containing at least one atom of nitrogen. Essential
VLDL particles (Despres 1998; Adiels et al. 2006; amino acids, i.e., those that cannot be synthesized
Fabbrini et al. 2009). in human cells, and nitrogen must be obtained
Interventions that decrease ectopic tissue lipid from diet to match amino acid requirement for
load are usually associated with improved insulin protein synthesis.
340 J.E. Galgani et al.
Dietary amino acids as well as those derived 5.2 Protein Turnover in Obesity
from endogenous protein hydrolysis are signifi-
cant energy substrates for humans, normally Theoretically, obesity-related hyperinsulinemia
corresponding to 10–20 % (70–100 g per day) of should promote protein accretion unless defective
total energy needs. As a by-product of amino acid insulin action also extends to amino acid utiliza-
oxidation, nitrogen is lost in urine, mainly in the tion. However, empirical demonstration of this
form of urea, implying that amino acids undergo- proposition has resulted inconclusive. In fact,
ing oxidation must be replaced by dietary amino many studies have been carried out to compare
acids. Thus, the balance between protein degrada- whole-body and tissue-specific amino acid metab-
tion (mainly assessed by nitrogen loss in urine), olism between lean and obese individuals. Some
synthesis, and intake is critical for preserving of these studies found that, in fasting condition,
whole-body lean mass. obese patients have increased protein degradation
Dietary amino acids reach the liver via portal in comparison with lean individuals (Nair
vein, and a significant proportion is retained by et al. 1983; Bruce et al. 1990; Welle et al. 1992;
hepatic tissue. Interestingly, branched-chain Chevalier et al. 2005); however, several other
amino acids (BCAA), i.e., valine, leucine, and studies did not confirm that finding (Luzi
isoleucine, are poorly metabolized by hepatocytes et al. 1996; Solini et al. 1997; Guillet
and are preferentially channeled to skeletal muscle et al. 2009). Upon insulin stimulation, obese sub-
for energy production as well as conversion into jects have either impaired (Jensen and Haymond
alanine and glutamine. These two latter amino 1991; Luzi et al. 1996) or unchanged (Caballero
acids are then released from muscle and taken up and Wurtman 1991; Welle et al. 1994; Solini
by the liver and other tissues for further utilization. et al. 1997; Chevalier et al. 2005) suppression of
Amino acid turnover is dependent on the level protein degradation.
of energy sufficiency that determines the extent at Regarding protein synthesis, similar controver-
which amino acids are spared as energy source sial results also exist (Luzi et al. 1996; Solini
including the balance between protein synthesis et al. 1997; Chevalier et al. 2005, 2006; Guillet
and degradation. Insulin is a key regulator of this et al. 2009). Therefore, it is uncertain what role
balance, although its effect depends on circulating plays insulin resistance in amino acid and
insulin concentration. Thus, low circulating insu- protein metabolism. Differences in study design
lin concentration (similar to observed in insulin- (e.g., adjustment in protein kinetic by body size,
sensitive fasted individuals) in the presence of relative versus absolute expression, insulin dose,
elevated amino acid supply stimulates muscle duration, etc.) as well as in subject characteristics
protein synthesis without affecting skeletal mus- including body fat distribution (Jensen and
cle protein breakdown (Greenhaff et al. 2008). Haymond 1991; Solini et al. 1997) can partly
However, increasing blood insulin concentration explain the lack of consistency across studies.
does not further enhance protein synthesis, while Alternatively, insulin regulation of glucose and
it strongly suppresses protein degradation amino acid metabolism may not lie on the same
(Greenhaff et al. 2008). molecular pathways or insulin dose-response
At the molecular level, insulin increases AKT kinetic.
(also referred as PKB) activity, which then
relieves the inhibition over mammalian target of
rapamycin (mTOR). As a consequence, the activ- 5.3 Branched-Chain Amino Acids
ity of eukaryotic initiation factor-binding protein (BCAA) and Obesity
1 (4E-BP1) and ribosomal protein S6 kinase
(p70S6K) increases leading ultimately to higher For over 50 years, it has been known that circu-
protein synthesis. Insulin also decreases protein lating BCAA concentration is elevated in human
degradation by inhibiting proteasome activity obesity (Newgard 2012). Even more, there is evi-
(Chondrogianni et al. 2014). dence suggesting that increased blood BCAA is
19 Carbohydrate, Fat, and Protein Metabolism in Obesity 341
an independent risk factor for insulin resistance macronutrients. Over the time, positive energy
(McCormack et al. 2013) and type 2 diabetes balance leads to a new steady state, set at a higher
(Wang et al. 2011); however, a mechanistic expla- energy flux levels, in which macronutrient over-
nation of these findings is elusive (Lynch flow matches macronutrient oxidation. Why when
and Adams 2014). Importantly, Everman individuals reach this new steady state cannot
et al. recently challenged the notion that BCAA resolve the metabolic disturbance associated
may actually be a causal determinant of insulin with excessive adiposity remains unknown.
resistance. Thus, they found that a short-term It is possible that abnormally high steady-state
infusion of BCAA in healthy individuals did not energy flux, attributed to increased body size
change insulin sensitivity (Everman et al. 2015). rather than to elevated physical activity, might
Still the question why blood BCAA is increased in itself determine metabolic stress. On the other
obesity and what is its pathophysiological rele- hand, tissue-specific metabolic disturbances
vance remain unsolved. One possible explanation may be undetectable when a whole-body
comes from the fact that most of dietary BCAA approach is utilized. On this regard, the fact that
reach peripheral circulation, which prompts the whole-body macronutrient oxidative and
idea that increased protein intake in obese indi- non-oxidative disposal under physiological con-
viduals may lead to higher circulating BCAA. ditions (e.g., in the transition from fasting to
Indeed, there is a tight direct correlation between feeding conditions or over a 24-h period) is fairly
BCAA intake and blood BCAA concentration similar in lean and obese individuals may
(Meguid et al. 1986a, b). underscore subtle tissue-specific macronutrient
Impaired tissue clearance of circulating BCAA unbalances.
might also play a role. In this regard, decreased It is very likely that our common notion of
content of enzymes involved in the oxidation of obesity as a single metabolic entity may be
BCAA in skeletal muscle biopsies of obese wrong. In fact, it has lately been described two
donors has been reported at the protein (Lefort types of obese individuals: the metabolically
et al. 2010) and the mRNA levels (Lackey healthy and unhealthy obese (Samocha-Bonet
et al. 2013). Furthermore, the content of mito- et al. 2014). The identification of tissue, cellular,
chondrial BCAA aminotransferase and and molecular determinants of metabolic adapta-
branched-chain keto acid dehydrogenase tion to high-energy fluxes will require the expan-
subunit E1 (two important catabolic enzymes of sion of our capabilities to study in vivo tissue
BCAA) was increased after gastric bypass- metabolic dynamics. It will be critical to identify
induced weight loss in the WAT of obese individ- the key biological features that promote metabolic
uals, and this was paralleled by a reduction in stress during overfeeding and weight gain and
circulating BCAA concentration (She understand the mechanisms underlying
et al. 2007). Although the possible contribution interindividual variation in the adaptation to over-
of WAT to whole-body BCAA metabolism seems feeding. Answering these questions should accel-
minor (Lackey et al. 2013), these studies suggest erate our comprehension of obesity-related
that high blood BCAA concentration in obesity metabolic disorders.
may not just be a consequence of higher food/
protein intake.
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