Hypothalamic Estrogen Signaling and Adipose Tissue Metabolism in Energy Homeostasis

Abstract

Obesity has become a global epidemic, and it is a major risk factor for other metabolic disorders such as type 2 diabetes and cardiometabolic disease. Accumulating evidence indicates that there is sex-specific metabolic protection and disease susceptibility. For instance, in both clinical and experimental studies, males are more likely to develop obesity, insulin resistance, and diabetes. In line with this, males tend to have more visceral white adipose tissue (WAT) and less brown adipose tissue (BAT) thermogenic activity, both leading to an increased incidence of metabolic disorders. This female-specific fat distribution is partially mediated by sex hormone estrogens. Specifically, hypothalamic estrogen signaling plays a vital role in regulating WAT distribution, WAT beiging, and BAT thermogenesis. These regulatory effects on adipose tissue metabolism are primarily mediated by the activation of estrogen receptor alpha (ERα) in neurons, which interacts with hormones and adipokines such as leptin, ghrelin, and insulin. This review discusses the contribution of adipose tissue dysfunction to obesity and the role of hypothalamic estrogen signaling in preventing metabolic diseases with a particular focus on the VMH, the central regulator of energy expenditure and glucose homeostasis.

Estrogen prevents age-dependent beige adipogenesis failure through NAMPT-controlled ER stress pathway

“…However, prolonged cold exposure also recruits Pdgfrb+ APCs to differentiate into beige adipocytes; a process that we did not investigate here ( 68 ). It also remains to be determined which of the three known estrogen receptors - ERα, ERβ, and G protein-coupled receptor 30 (GPR30), all of which are expressed in the adipose tissue ( 42 ) - mediates estrogen signaling to promote beige adipogenesis within Sma+ cells. Nonetheless, our findings begin to pave the way for a novel estrogen-based cellular therapy to address the negative impacts of aging.…”

“…Estrogens play significant developmental and functional roles in many organs of male and female humans, respectively ( 40, 41 ). Specifically, estrogen controls whole-body metabolism through central and peripheral mechanisms by the activation of estrogen receptors (ERα and ERβ) ( 42 ). The loss of estrogen and knocking out ERα in mice is associated with adipose tissue redistribution, impaired glucose homeostasis, insulin resistance, and elevated type 2 diabetes risks ( 42 ).…”

“…Specifically, estrogen controls whole-body metabolism through central and peripheral mechanisms by the activation of estrogen receptors (ERα and ERβ) ( 42 ). The loss of estrogen and knocking out ERα in mice is associated with adipose tissue redistribution, impaired glucose homeostasis, insulin resistance, and elevated type 2 diabetes risks ( 42 ). This is evident by the higher diabetes incidence in men and postmenopausal women versus premenopausal women ( 43, 44 ).…”

Neuregulin 4 as a novel adipokine in energy metabolism

“…Adipose tissue has a vital role in energy metabolism and homeostasis and adipose tissue dysfunction have been proven to lead to metabolic diseases such as obesity and diabetes ( Torres Irizarry et al, 2022 ). Adipose tissue is traditionally divided into white adipose tissue (WAT) and BAT, and recently a new type of thermogenic adipocyte, the beige adipocyte, has been proposed ( Wu et al, 2012 ).…”

The evolutionary impact and influence of oestrogens on adipose tissue structure and function

“…Speakman suggests accrual of body adiposity provides a selective advantage for sustaining metabolic processes, fighting illness and supporting physical activity [4]. It appears oestrogens are critical drivers of these functions, which is why women can store fat and extra calories more healthily than men, a phenomenon that leads to reductions in disease prevalence in pre-menopausal women when compared to men [4][5][6].…”