Adaptations in physiological and neuronal function during diet-induced obesity

Abstract

Obesity significantly increases the risk of developing chronic conditions including type II diabetes, cardiovascular disease, and some cancers. The rate of obesity has tripled globally since 1975, which is in part due to the sudden prevalence and overconsumption of palatable high-fat diets (HFDs). Obesity profoundly perturbs the neural control of energy balance, affecting diverse cell types within the hypothalamus. However, an incomplete understanding of how HFD impacts the regulation of energy balance hinders our ability to more effectively treat obesity. In this thesis, I describe the physiological and neuronal response to HFD feeding in rodents. We identified that HFD exposure elevates the body weight set point, which is initially driven by a transient hyperphagia. This hyperphagia coincides with increased excitatory transmission to lateral hypothalamic orexin (ORX) neurons, which regulate acute food intake. This suggests that ORX neurons may be involved in the initial hyperphagia, implicating them in the development of obesity. As HFD prolongs, body weight gain slows and reaches a new steady state regardless of age at the start, duration of feeding, or palatability of the diet. This sustained weight coincides with increased synaptic contacts to melanin-concentrating hormone (MCH) neurons, which promote weight gain and food intake, likely contributing to the maintenance of obesity. The molecular mechanism underlying the establishment of a new set point remains elusive. During HFD feeding, the presence of a chronic low-grade hypothalamic inflammation exacerbates weight gain, therefore we reasoned that inflammatory factors could modulate appetite-promoting neurons to maintain a new set point. We found that the inflammatory mediator prostaglandin E2 (PGE2) activate MCH neurons via its EP2 receptor (EP2R). Suppressing PGE2-EP2R on MCH neurons partially protects against excess weight gain and fat accumulation in the liver during HFD feeding. This mechanism could contribute to the maintenance of an elevated body weight set point in during diet-induced obesity. Without long-term treatment options in face of the increasing rates of obesity, we are in desperate need of novel interventions. In the future, we hope that targeting EP2R on MCH neurons can lower body weight set point and aid in combatting obesity.