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.
Highlights
The global prevalence of obesity is rapidly increasing with an estimated 2.1 billion people considered overweight or obese (Tremmel, Gerdtham, Nilsson, & Saha, 2017)
Energy homeostasis involves co‐ordination of various metabolic signals emanating from the peripheral organs as well as the central nervous system (Lenard & Berthoud, 2008; Pimentel et al, 2012)
The hypothalamus plays an integral role in regulating whole‐body energy metabolism and controls many important physiological functions, with neurons of the arcuate nucleus (ARC) being essential for controlling food intake and energy expenditure (Lenard & Berthoud, 2008). The function of these neurons is modulated through the action of several hormones including leptin and insulin, both of which are involved in controlling energy homeostasis, playing crucial roles in regulating lipid and glucose metabolism, respectively (Belgardt & Bruning, 2010)
Summary
The global prevalence of obesity is rapidly increasing with an estimated 2.1 billion people considered overweight or obese (Tremmel, Gerdtham, Nilsson, & Saha, 2017). The function of these neurons is modulated through the action of several hormones including leptin and insulin, both of which are involved in controlling energy homeostasis, playing crucial roles in regulating lipid and glucose metabolism, respectively (Belgardt & Bruning, 2010) Hypothalamic repression of their hormonal function results in dysregulated signaling, systemically affecting the major organs, manifesting as obesity, and metabolic syndrome (MeS) (Marino, Xu, & Hill, 2011; Morton & Schwartz, 2011). Most research has evaluated maternal role in epigenetic inheritance (Soubry, 2015), especially with regard to DNA methylation and its role in obesity pathophysiology Such studies have revealed that offspring of obese mothers exhibit elevated body fat, leptin cord blood, and cytokine levels (Catalano, Presley, Minium, & Hauguel‐de Mouzon, 2009), together with increased insulin, cholesterol, and blood pressure (Gaillard, 2015). TA B L E 1 Animal studies examining the effect of obesogenic diets on DNA methylation and gene expression profiles within the arcuate nucleus
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