OBESITY AND

IMMUNE
FUNCTION
Recommended readings
Recommended readings

https://www.jci.org/articles/view/88876
 Obesity : an epidemic
• The prevalence of obesity has increased dramatically
over the past three decades (is the greater public
health problem in the western world) and has
contributed to the increasing prevalence of:
– insulin resistance (IR)
– type 2 diabetes (T2D)
– cardiovascular disease
INFLAMMATION
INFLAMMATION
– fatty liver/cirrhosis
– hypertension
– cancer
– chronic autoimmune and inflammatory pathologies
Obesity : an epidemic

SOURE: https://www.fastcompany.com/301
Visceral versus subcutaneous
abdominal fat
Visceral versus subcutaneous
abdominal fat
LOWEST RISK MODERATE RISK HIGHEST RISK
 Adipose tissue
Certain food
compounds can
promote BAT
activation and WAT
browning

El Hadi H, et al., 2019. Front. Physiol. 9:1954.

Adipose tissue

Choe et al., 2016, Front. Endocrinol. 7:30.

 Adipose tissue inmmune cells
• Adipose tissue is an active endocrine organ and a
real immune organ, not only a simple energy
storage tissue.
• It is constituted by: Huh, J.Y., et al., 2014, Mol. Cells 2014; 37(5): 365-371

o adipocytes
o fibroblasts
o endothelial cells
o immune cells:
ü macrophages
ü neutrophils
ü mast cells
ü eosinophils
ü T and B cells
 Adipose tissue in obesity
• Obesity is characterized by chronic low-grade
inflammation associated with a dysfunctional fat
mass.

Dludla, P.V.; Nkambule, B.B.; Jack, B.; Mkandla, Z.; Mutize, T.; Silvestri, S.; Orlando, P.; Tiano, L.; Louw, J.; Mazibuko-Mbeje, S.E.
Inflammation and Oxidative Stress in an Obese State and the Protective Effects of Gallic Acid. Nutrients 2019, 11, 23.
 Adipose tissue in obesity
• AT releases adipokines, crucial players in:
o Energy metabolism
o Inflammation and immunity
ADIPOKINES RELEASED
by AT
↑↑ in obesityà LGI

Gustafson et al., 2007, Arterioscler Thromb Vasc

Biol. 2007;27:2276-2283
 WAT expansion in obesity
• In obesity the expanded trunkal AT à cascade of events
causing a local inflammatory response which very rapidly
spreads systemically.

Longo et al., 2019 Int. J. Mol. Sci., 20, 2358

WAT expansion in obesity

↑Visceral A.T
+
hypertrophia

⇩
Metabolic
dysfunction

Cytoskeleton
alteration à
altered Glc
metabolism

Choe et al., 2016, Front. Endocrinol. 7:30.

Changes in immune cell content and function
in AT in obese

Choe et al., 2016. Front. Endocrinol. 7:30.

Changes in immune cell content and function
in AT in obese

ANTINFLAMMATORY PRO-INFLAMMATORY
McLaughlin et al., : J Clin Invest. 2017;127(1):5–13
 Invariant natural killer T (iNKT) cell-mediated
regulation of anti-inflammatory response in the AT.

Choe et al., 2016. Front. Endocrinol. 7:30.

Process and involvement of adipose tissue, immune cells
and cytokines in the inflammatory process that trigger
local IR.

Rodríguez López y col. 2017 Investigación Clínica 58(2):176-195

Jack et al., 2019 Biomed&Pharmacother. 120: 109439
 IR plays a
central role in
obesity
comorbidities

Esser N, et al. Diabetes Res Clin Pract (2014)

 Adipose
Tissue
remodeling
and obesity
Sun et al., J
Clin Invest.
2011;121(6):2
094–2101

(A) Healthy AT expansion consists of an enlargement of AT through effective recruitment of

adipogenic precursor cells to the adipogenic program, along with an adequate angiogenic
response and appropriate remodeling of the ECM. There are strong individual differences with
respect to the potential for ATexpansion.
(B) Pathological AT expansion consists of massive enlargement of existing adipocytes, limited
angiogenesis, and ensuing hypoxia. As a result, HIF-1α is induced, which in turn can cause
the induction of a fibrotic program. Ultimately, M1-stage macrophages prevail, leading to an
inflammatory phenotype that is strongly associated with systemic insulin resistance.
 IR plays a central role in obesity
comorbidities

Paniagua, Juan. (2016). Nutrition, insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome. World
Journal of Diabetes. 7. 483.
Inmunofenotipo de las células inmunes en el tejido
adiposo hipertrofiado y evolución de las células
del sistema inmune en el TA en la obesidad

Rodríguez López y col. 2017 Investigación Clínica 58(2):176-195

 ADIPONECTIN
• Adiponectin is an adipose-derived plasma protein
with widespread effects.

• FUNCTIONS: anti-atherogenesis, insulin sensitization,

lipid oxidation enhancement, and vasodilatation.

• So it is related to metabolic syndrome given its

impact on all of these components.

• Unlike leptin, it is secreted exclusively from

adipocytes
ADIPONECTIN

Nagaraju et al., 2016

https://doi.org/10.1016/j.cytogfr.2016.03.014
Lau et al., 2017
 ADIPONECTIN and IS
• In obese individualsà adipocytes are overloaded with
lipidsà produce ↑amounts of leptin and ↓ amounts
of adiponectin.
• Adiponectin has direct effects on immune cells.
• Adiponectin attenuates immune responses primarily
by suppressing macrophage activation à

Maintains immune homeostasis by avoiding

hyperactivation of macrophages in response to
pathogens or endogenous stimuli such as apoptotic
cells or microbiota in the intestinal tract.
 Leptin and obesity
• Leptin, the best-characterized member of adipokine
family
• It exerts its physiological activity through the LEPR or
Ob-R (at least six LEPR isoforms).

• It is produced mostly by
adipocytes, but also by
vascular smooth muscle
cells, cardiomyocytes,
and placenta.

Francisco et al., 2018. Front. Physiol.

 Leptin and obesity
• This hormone, together with other regulatory
molecules, has a central role in appetite and
body weight homeostasis.
• Under normal physiological conditions
functions to:
Ø ↓appetite
Ø ↑energy expenditure
Ø ↑sympathetic activity
Ø facilitate glucose utilization
Ø improve insulin sensitivity
Leptin, immune response and obesity
• Leptin plays a regulatory role in the interplay between
energy metabolism and the immune system.

• It’s one of the adipokines responsible for the

inflammatory state found in obesity that predisposes
to:
Ø type 2 diabetes
Ø metabolic syndrome
Ø NAFLD
Ø cardiovascular disease
Ø Bone diseases (OA, RA)
Ø autoimmune and allergic diseases
 Leptin, immune response and obesity
[Plasma leptin] à biological marker of the inflammatory status
and the onset and evolution of pathologies associated with
dysregulation of the immune system.

Front. Physiol., 01 June 2018 |

https://doi.org/10.3389/fphys.2018.00640
Leptin and innate & adaptative IS

Francisco et al. 2018

Leptin, adiponectin and obesity

Richi and Bevilacqua, 2012.

 Leptin resitance
• Central leptin resistance is considered the main
risk factor for the obesity pathogenesis.
• CLR can be caused by :
– impairment of leptin transportation
– leptin signaling
– leptin target neural circuits
• Leptin release is modulated in a circadian rhythm
manner.
• LEPR is expressed in across the cells of innate
and adaptive immune systemà crucial linker of
neuroendocrine and immune systems.
Sáinz et al., 2015, Metabolism, 64
(1): 35-46
Leptin also affects other physiological functions

Front. Physiol., 01 June 2018 | https://doi.org/10.3389/fphys.2018.00640

 Immunometabolism as a new
research discipline
• Metabolic status of immune cells directly determines
their function and differentiationà affecting
immunity and toleranceà autoimmune pathologies

• Innate and adaptive immune cells adapt to altered

tissue microenvironment (hypoxia and nutrient
competition) à reprogramming their metabolism

Failure in this metabolic

reconfiguration àderegulated immune
response and pathology.
OBESITY AND IMMUNE
FUNCTION
Extra bibliography
•Cerf-Bensussan, N., & Gaboriau-Routhiau, V. (2010). The immune system and the gut
microbiota: friends or foes? Nature Reviews Immunology, 10, 735-744.

•Francisco V, Pino J, Campos-Cabaleiro V, Ruiz-Fernández C, Mera A, Gonzalez-Gay MA,

Gómez R and Gualillo O (2018) Obesity, Fat Mass and Immune System: Role for Leptin.
Front. Physiol. 9:640.

•Fung, T., Olson, C. & Hsiao, E. (2019) Interactions between the microbiota, immune and
nervous systems in health and disease. Nat Neurosci 20, 145–155.

•Goossens GH 2017: The Metabolic Phenotype in Obesity: Fat Mass, Body Fat
Distribution,and Adipose Tissue Function. Obes Facts;10:207–215

•Holvoet, P. (2012). Stress in Obesity and Associated Metabolic and Cardiovascular

Disorders. Scientifica. 2012. 205027.

•Liu R and Nikolajczyk BS (2019) Tissue Immune Cells Fuel Obesity-Associated

Inflammation in Adipose Tissue and Beyond. Front. Immunol. 10:1587.

•Srikanthan1 K, Feyh1 A., Visweshwar1 H., Shapiro1 JI. and Sodhi K. (2016)Int. J. Med.
Sci. 13(1): 25-38.
WESTERN DIET AND
IMMUNE SYSTEM
ALTERATIONS
 Mice model

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324559/
 Western diets and IS
• The Western diet is characterized by:
– a high intake of saturated and omega-6 fatty acids
– reduced omega-3 fat intake
– an overuse of salt Proinflammatory
scenary
– too much refined sugar

• Modern diet also damages the immune system

 Western diets and IS
• The modern lifestyle is also typified by:
– reduced exposure to microorganisms
– increased exposure to pollutions
– heightened levels of stress
– other factors contribute to immune dysfunction

Dietary effects on immunity should not be

thought of in isolation to determine the
mechanisms for the Western diet’s impact on
immune function.
Myles, 2014
 Myles Nutrition Journal 2014, 13:61
http://www.nutritionj.com/content/13/1/61