Forebrain-Hypothalamic Circuits, Endoplasmic Reticulum Stress, and Sexual Dimorphism in Hepatic Steatosis During Obesity
Open AccessAssociated with the epidemic of obesity, non-alcoholic fatty liver disease (NAFLD) affects 1 in 3 American adults. NAFLD is characterized by hepatic triglyceride accumulation and leads to an increased risk for type II diabetes, insulin resistance and obesity-related mortality. Thus, understanding the underlying mechanisms contributing to NAFLD is a priority. While the majority of investigations have taken a liver-centric perspective it is critical to consider a role for the central nervous system in hepatic pathophysiology. Recent findings indicate that alterations in the subfornical organ (SFO), a forebrain sensory circumventricular region, mediates hepatic steatosis during obesity. Importantly, the SFO has dense excitatory projections to the paraventricular nucleus of the hypothalamus (PVN), an integrative nucleus that plays a critical role in autonomic and endocrine control. However, the downstream neural circuits, and neuronal molecular mechanisms involved in this response, remain unclear. This dissertation seeks to anatomically, molecularly and physiologically characterize a previously unrecognized forebrain-hypothalamic-autonomic circuit, in the pathogenesis of NAFLD. Changes in the anatomical structure of brain networks leads to functional alterations. In this context, electron microscopy can provide nanometer resolution of normal/abnormal brain structures and individual organelles. The first study describes the development and utilization of a novel large field of view high-resolution backscatter scanning electron microscopy technique. This technique includes the development of zoomable, Google map-like image sets to integrate cellular/organelle location within the overall PVN with ultrastructural detail. This technique was developed to subsequently evaluate endoplasmic reticulum ultrastructure in Aim two. There is mounting evidence that endoplasmic reticulum stress and activation of the unfolded protein response (UPR) are involved in the generation and propagation of NAFLD. Our recent findings indicate that UPR activation in the brain mediates hepatic steatosis during obesity in male mice. Our preliminary findings also point to elevations in hepatic sympathetic nerve activity as a key driver of NAFLD. We build upon these findings in the second series of studies and show that chemogenetic activation of SFO neurons that project to the PVN results in elevations in hepatic sympathetic outflow that is accompanied by the development of NAFLD. To investigate the molecular mechanism involved in this response we turned to a diet induced obesity model of NAFLD and found that high fat diet feeding results in endoplasmic reticulum ultrastructural abnormalities in PVN neurons that is paralleled by increased gene and protein expression of key UPR markers. We further demonstrate that excitatory signaling from the SFO drives endoplasmic reticulum stress in the PVN. Importantly, overexpression of the endoplasmic reticulum chaperone glucose-regulatory protein 78 in the PVN during obesity relieves hepatic steatosis. Taken together, these findings characterize a previously unrecognized forebrain-hypothalamic-ER stress circuit that is involved in hepatic steatosis, which may point to future therapeutic strategies for NAFLD. The final study explores the role of the central nervous system (CNS) in the sexual dimorphism of NAFLD. Although the etiology of NAFLD is multifactorial, sexual dimorphism is clearly established. Pre-menopause, women show significantly lower prevalence of NAFLD and other metabolic comorbidities when compared to age-matched men. However, following menopause, the rate of NAFLD is equal between men and women, suggesting circulating estrogen plays a protective role in fertile women. Most work to date has been based on the loss of estrogen in females (e.g. menopause). Interestingly, transgender individuals receiving feminizing gender affirming therapy (i.e. estrogen) appear to be relatively protected from metabolic syndrome conditions. Furthermore: 1) CNS estrogen is critically involved in metabolic regulation; and 2) CNS estrogen receptors in several nuclei are present at the same density in males and females. We used a unique model where obese male mice were supplemented with intracerebroventricular 17-estradiol. The findings suggest that short-term central estrogen supplementation in obese male mice is an effective means to reduce body weight, food intake, visceral adiposity, and hepatic steatosis. These data may help explain why premenopausal females and transgender females are relatively protected from metabolic syndrome conditions such as NAFLD. The studies in this dissertation are highly innovative on several levels, both in concept and approach. While it has long been known that the brain is intimately involved in peripheral metabolic regulation, these results support a previously unrecognized forebrain-hypothalamic circuit involving the SFO and the PVN that modulates hepatic metabolism through sympathetic outflow. This circuit is of particular interest as the SFO lies outside the blood brain barrier, making it open to circulating factors, including pharmacological agents. Thus, this work has the potential to lead to new therapeutic targets in the fight against NAFLD and metabolic syndrome as a whole.
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