Sexual Dimorphism in Adipose-Hypothalamic Crosstalk and the Contribution of Aryl Hydrocarbon Receptor to Regulate Energy Homeostasis

Abstract

There are fundamental sex differences in the regulation of energy homeostasis. Better understanding of the underlying mechanisms of energy balance that account for this asymmetry will assist in developing sex-specific therapies for sexually dimorphic diseases such as obesity. Multiple organs, including the hypothalamus and adipose tissue, play vital roles in the regulation of energy homeostasis, which are regulated differently in males and females. Various neuronal populations, particularly within the hypothalamus, such as arcuate nucleus (ARC), can sense nutrient content of the body by the help of peripheral hormones such leptin, derived from adipocytes, to regulate energy homeostasis. This review summarizes how adipose tissue crosstalk with homeostatic network control systems in the brain, which includes energy regulatory regions and the hypothalamic–pituitary axis, contribute to energy regulation in a sex-specific manner. Moreover, development of obesity is contingent upon diet and environmental factors. Substances from diet and environmental contaminants can exert insidious effects on energy metabolism, acting peripherally through the aryl hydrocarbon receptor (AhR). Developmental AhR activation can impart permanent alterations of neuronal development that can manifest a number of sex-specific physiological changes, which sometimes become evident only in adulthood. AhR is currently being investigated as a potential target for treating obesity. The consensus is that impaired function of the receptor protects from obesity in mice. AhR also modulates sex steroid receptors, and hence, one of the objectives of this review is to explain why investigating sex differences while examining this receptor is crucial. Overall, this review summarizes sex differences in the regulation of energy homeostasis imparted by the adipose–hypothalamic axis and examines how this axis can be affected by xenobiotics that signal through AhR.

Deficiency of Adipose Aryl Hydrocarbon Receptor Protects against Diet-Induced Metabolic Dysfunction through Sexually Dimorphic Mechanisms

“…These sex-specific differences also manifest in disease pathology. While females are more prone to obesity, males are more susceptible to obesity-related comorbidities, such as type 2 diabetes [ 4 , 40 ].…”

“…In addition to acting as a lipid storage depot, WAT is an active endocrine organ that secretes adipokines and adipocytokines to communicate with various other organs to influence systemic metabolism. Information regarding substrate availability, tissue mass, energy intake, and utilization is reported to the brain by adipose tissue [ 3 , 4 ]. The brain responds by making necessary changes to maintain the body homeostasis including energy balance.…”

Female obesity: clinical and psychological assessment toward the best treatment

“…Indeed, female brain presents increased POMC neuronal fibers, higher levels of the POMC protein and decreased NPY expression compared to males. Accordingly, while testosterone stimulates NPY expression in the hypothalamus in males, in females estradiol impairs the excitability of the NPY neurons (29). In addition, leptin concentrations are four times higher in women (30), and in rat models female brain is more sensitive to leptin, while male brain is more sensitive to insulin (31).…”