Obesity Knowledge Challenge: Genetics, Physiology, and Risk Factors

White adipose tissue is the main cell type found in humans; is composed of adipocytes, adipocyte precursors, endothelial cells, and immune cells; and stores excess calories as triglycerides and cholesterol esters. White adipose tissue expansion contributes to obesity and obesity-related comorbidities. Brown adipose tissue regulates energy expenditure through various forms of thermogenesis. Deposition and function of brown adipose tissue vary according to age.

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Fitch AK et al. Differentiating monogenic and syndromic obesities from polygenic obesity: Assessment, diagnosis, and management. Obes Pillars. 2024 Apr 22;11:100110. doi:10.1016/j.obpill.2024.100110. Accessed August 17, 2025. Differentiating monogenic and syndromic obesities from polygenic obesity: Assessment, diagnosis, and management - PMC

Whereas a substantial proportion of the global population has polygenic obesity, monogenic and syndromic obesities are rare, with some variants affecting only hundreds of people. Polygenic obesity arises from interactions between multiple gene variants and an environment that may facilitate development of obesity, while monogenic and syndromic obesities can be caused by a single gene variant. Monogenic and syndromic obesities commonly occur before 5 years of age; polygenic can occur at any age. Polygenic obesity is diagnosed on the basis of BMI, but monogenic and syndromic obesities typically require genotyping and analysis of genetic variants for diagnosis.

Source:

Fitch AK et al. Differentiating monogenic and syndromic obesities from polygenic obesity: Assessment, diagnosis, and management. Obes Pillars. 2024 Apr 22;11:100110. doi:10.1016/j.obpill.2024.100110. Accessed August 17, 2025. Differentiating monogenic and syndromic obesities from polygenic obesity: Assessment, diagnosis, and management - PMC

Leptin is an adipokine that regulates appetite, neuroendocrine function, and metabolism based on energy availability. Leptin is secreted by adipose tissue and communicates with the hypothalamus to regulate satiety and energy expenditure. In normal physiology, higher fat stores increase leptin levels, resulting in reduced appetite. However, in obesity, individuals often develop leptin resistance, which contributes to persistent overeating, reduced energy expenditure, and further weight gain.

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Stefanakis K et al. Leptin physiology and pathophysiology in energy homeostasis, immune function, neuroendocrine regulation and bone health. Metabolism. 2024 Dec:161:156056. doi:10.1016/j.metabol.2024.156056. Accessed August 17, 2025. Leptin physiology and pathophysiology in energy homeostasis, immune function, neuroendocrine regulation and bone health - PubMed

POMC (proopiomelanocortin) deficiency is a monogenetic disorder, and the others are syndromic forms of obesity. Early onset of severe obesity and the presence of hyperphagia are the 2 clinical characteristics that distinguish genetic disorders of obesity. Early onset refers to the presence of obesity before 5 years of age. Hyperphagia is the presence of insatiable hunger in which the time to satiation is long, the duration of satiation is shorter, feelings of hunger are prolonged, and a severe preoccupation with food exists along with distress if food is denied. Characteristics of POMC deficiency include accelerated childhood growth, adrenocorticotropic hormone deficiency, mild hypothyroidism, red hair, and light skin (in non-Hispanic white individuals).

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Hampl SE et al. Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents With Obesity. Pediatrics. 2023 Feb 1;151(2):e2022060640. doi:10.1542/peds.2022-060640. Accessed August 17, 2025. Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents With Obesity | Pediatrics | American Academy of Pediatrics

According to data from the National Health and Nutrition Examination Survey, those with a waist-to-hip ratio (WHR) indicative of central obesity have a higher risk of cardiovascular mortality than those with the same BMI but without central obesity. Even in individuals with normal weight, a high waist circumference (WC) may be associated with a higher risk of cardiovascular disease. The World Health Organization (WHO) reference values for WHR are the ones most widely used: for men, WHR >0.90 = central obesity; for women, WHR >0.85 = central obesity.

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Powell-Wiley TM et al. Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2021 Apr 22;143(21):e984–e1010. doi:10.1161/CIR.0000000000000973. Accessed August 17, 2025. Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association - PMC

Waist Circumference and Waist-Hip Ratio: Report of a WHO Expert Consultation. Geneva. December 8-11, 2008. World Health Organization. 2011. Accessed August 17, 2025. 9789241501491_eng.pdf