Neuroendocrinology and the Genetics of Obesity

The increase in the incidence of obesity has coincided with changes in lifestyle, diet, and environment. Comorbidities associated with obesity include cardiovascular disease, diabetes, musculoskeletal disorders, stroke, and thromboembolism, affecting public health. The effect of increased weight has recently become even more obvious, since obesity has been significantly associated with increased severity and higher mortality among COVID-19 patients. The need to decrease rates of obesity prompted a surge in the use of glucagon-like peptide-1 agonist medications. Twin studies, however, determined that increased weight has a large genetic component, estimating the heritability of obesity to be 45% to 70%. Surprisingly, obesity due to known single gene mutation comprises only 5% to 10% of individuals, who mostly exhibit early-onset severe obesity. Genome-wide linkage studies and association studies identified more than 250 genes associated with obesity, but each of these has a relatively small effect size. Further, several genetic syndromes, associated with neurodevelopmental disabilities and congenital malformations, encompass obesity in their constellation of symptoms. This review will summarize several known genetic causes of obesity, focusing specifically on how they relate to the brain circuitry that regulates food intake and energy homeostasis. The review will indicate a need for further studies to integrate the role of diet and environmental contribution with genetic components of this multifactorial condition. Given that genetics of obesity is unlikely to explain the recent dramatic temporal increase in the prevalence of obesity, our review will point to the need to understand interactions between genes and other contributing environmental or sex-dependent factors.