Diet‐induced DNA methylation within the hypothalamic arcuate nucleus and dysregulated leptin and insulin signaling in the pathophysiology of obesity

Abstract

Obesity rates continue to rise in an unprecedented manner in what could be the most rapid population‐scale shift in human phenotype ever to occur. Increased consumption of unhealthy, calorie‐dense foods, coupled with sedentary lifestyles, is the main factor contributing to a positive energy balance and the development of obesity. Leptin and insulin are key hormones implicated in pathogenesis of this disorder and are crucial for controlling whole‐body energy homeostasis. Their respective function is mediated by the counterbalance of anorexigenic and orexigenic neurons located within the hypothalamic arcuate nucleus. Dysregulation of leptin and insulin signaling pathways within this brain region may contribute not only to the development of obesity, but also systemically affect the peripheral organs, thereby manifesting as metabolic diseases. Although the exact mechanisms detailing how these hypothalamic nuclei contribute to disease pathology are still unclear, increasing evidence suggests that altered DNA methylation may be involved. This review evaluates animal studies that have demonstrated diet‐induced DNA methylation changes in genes that regulate energy homeostasis within the arcuate nucleus, and elucidates possible mechanisms causing hypothalamic leptin and insulin resistance leading to the development of obesity and metabolic diseases.

Time-of-Day-Dependent Effects of Bromocriptine to Ameliorate Vascular Pathology and Metabolic Syndrome in SHR Rats Held on High Fat Diet

“…Among ZT 13 bromocriptine-treated animals, the hypothalamic levels of AgRP and NPY mRNAs were markedly reduced by 57 and 48%, respectively, relative to controls, and such reductions were concurrent with a marked 86% reduction in circulating leptin levels. Inasmuch as leptin and insulin are potent inhibitors of arcuate neuronal AgRP and NPY expression and activity under normal metabolic conditions [ 89 , 90 , 91 , 92 ], and these neurons lose their responsiveness to such leptin and insulin actions during high fat feeding and obesity [ 93 , 94 , 95 , 96 , 97 ], these present findings strongly imply an improvement in AgRP/NPY neuronal leptin and insulin sensitivity to reduce AgRP and NPY expression, even during prolonged high fat diet feeding by ZT 13 bromocriptine treatment. However, although ZT 19 bromocriptine treatment similarly reduced MBH AgRP expression as ZT 13 BC, it was without effect upon MBH NPY mRNA expression and plasma insulin and leptin, (see Figure 2 and Figure 3 ).…”

Revisión de la obesidad como concepto científico (Obesity review as a scientific concept)

“…El costo resultante de la obesidad y sus comorbilidades ha sido muy alto, tanto por los costos médicos directos como por la pérdida de productividad asociada con las morbilidades y la muerte prematura (Samodien, Pheiffer, Erasmus, Mabasa, Louw & Johnson, 2019;Heindel & Blumberg, 2019).…”

“…La represión hipotalámica de su función hormonal da como resultado una señalización desregulada, que afecta sistémicamente a los órganos principales, manifestándose como obesidad y síndrome metabólico. Recientemente se ha identificado que la ingesta excesiva de grasas animales provoca inflamación microglial y estrés celular, como el estrés del retículo endoplásmico y estrés oxidativo en el hipotálamo, paralizando el sistema regulador del hambre metabólica, surgiendo así una condición en la que el cerebro no puede juzgar correctamente la ingesta de energía adecuada para el cuerpo (Masuzaki, et al, 2019;Samodien, et al, 2019).…”

Association between methyl donor nutrients and metabolic health status in overweight and obese adolescents

“…Some nutrients including vitamins B2, B6, B9, B12, methionine, betaine and choline are defined as methyl donors due to their roles in a series of reactions known as the methylation cycle in which a methyl group can go on and attach to different molecules and regulate several processes 16 . Epigenetic mechanisms such as DNA methylation play an important role in leptin secretion as well as regulation of metabolic enzymes and can subsequently be involved in metabolic disorders 17 . Also, the conversion of homocysteine to methionine is dependent to the one-carbon methylation cycle, and disruption of this process can result in hyperhomocysteinemia and its related diseases 16 .…”