Obesity Is a Disease

Pathophysiology of Obesity

Dysregulation of Energy Homeostasis Contributes to Obesity Development and Persistence

Emerging data suggests that the neuroendocrine regulation of central nervous system (CNS) pathways involved with food intake, energy expenditure, and body weight may be impaired in obesity.¹ Under normal physiologic conditions, the dietary energy intake required to maintain energy homeostasis varies by age, gender, body size, genetic factors, activity, and ambient temperature.² These inter- and intra-individual variations in energy needs are, in principle, reflected in appetite and food intake.³ Prolonged imbalance in energy homeostasis is the fundamental cause for pathophysiological changes observed during obesity.⁴ Excess energy is stored as lipid in adipocytes, and chronic positive energy balance may lead to either adipocyte hyperplasia (increased number of adipocytes) or adipocyte hypertrophy (increased size of adipocytes).⁵

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Increased lipid storage in adipocytes leads to adipocyte hypertrophy and dysfunction, leading to increased circulating lipids.

Subcutaneous Adipose Tissue (SAT), Visceral Adipose Tissue (VAT), and Ectopic Fat in Obesity

Healthy storage of the excess energy from the diet into subcutaneous adipose tissue (SAT) is possible when SAT has the ability to expand through hyperplasia (generation of new fat cells). When this process becomes saturated, or the ability of adipose tissues to expand becomes limited, adipocyte hypertrophy may occur, leading to a spillover of excess energy. This excess energy can be stored in visceral adipose tissue (VAT), surrounding intraabdominal organs, as well as in organs (a process known as ectopic fat deposition).⁶ Evidence suggests that adverse metabolic risk factors are more often associated with visceral fat than subcutaneous fat.⁷ Typically, adipocytes produce adipokines such as leptin, adiponectin, and resistin – molecules involved in energy balance regulation. The production of these adipokines appears to be altered in adipocyte hypertrophy.^8,9

Adipocyte hypertrophy leads to visceral and subcutaneous fat accumulation.

Expansion of Adipocyte Volume to Accommodate More Lipids

Adipocyte hypertrophy induces adipocyte dysfunction by creating stress within the endoplasmic reticulum and mitochondria. This is associated with the production of proinflammatory mediators (TNF-α, IL-6, sRBP-4, and CRP), altered synthesis of adipokines, and increase in circulating free fatty acid levels.⁸ Increased free fatty acids in circulation may lead to lipid accumulation within the liver, heart, skeletal muscle, and pancreas, contributing to local and systemic inflammation and insulin resistance.¹⁰

Accumulation of visceral and subcutaneous fat leads to obesity.

Abnormal Accumulation of Subcutaneous and Visceral Fat Leads to Obesity-Related Complications

Adipocyte dysfunction and altered adipokine production play a prominent role in the pathophysiology of obesity-related complications.^8,9 Altered adipokine profile, and production and secretion of proinflammatory cytokines, contributes to local and systemic inflammation. In turn, these processes contribute to the initiation and progression of several metabolic disorders such as type 2 diabetes, cardiovascular disease, MAFLD (NAFLD), and certain cancer types.¹¹

CRP=C-Reactive Protein; IL-6=Interleukin 6; MAFLD=Metabolic Dysfunction-Associated Fatty Liver Disease; NAFLD=Non-alcoholic Fatty Liver Disease; sRBP-4=Serum Retinol Binding Protein 4; TNF-α=Tumor Necrosis Factor Alfa.

References

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National Research Council (US) Subcommittee. 3. Energy. Recommended Dietary Allowances: 10th Edition. National Academies Press (US). 1989;24-38.
Borrelli R, Simonetti MS, Fidanza F. Inter- and intra-individual variability in food intake of elderly people in Perugia (Italy). Br J Nutr. 1992;68(1):3-10.
Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol. 2019;15(5):288-298.
Longo M, Zatterale F, Naderi J, et al. Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications. Int J Mol Sci. 2019;20(9):2358.
Drolet R, Richard C, Sniderman AD, et al. Hypertrophy and hyperplasia of abdominal adipose tissues in women. Int J Obes (Lond). 2008;32(2):283-291.
Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation. 2007;116(1):39-48.
de Ferranti S, Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem. 2008;54(6):945-955.
Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol. 2010;314(1):1-16.
Ahmed B, Sultana R, Greene MW. Adipose tissue and insulin resistance in obese. Biomed Pharmacother. 2021;137:111315.
Gutiérrez-Cuevas J, Santos A, Armendariz-Borunda J. Pathophysiological molecular mechanisms of obesity: a link between MAFLD and NASH with cardiovascular diseases. Int J Mol Sci. 2021;22(21):11629.

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Pathophysiology of Obesity

References

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