UC Riverside

Obesity is a chronic disease that is increasingly becoming a global public health concern. Obesity is associated with type 2 diabetes, cardiovascular disease, stroke and endocrine abnormalities. In addition, there are sex differences in obesity mediated pathologies, such as obese men are more at risk for developing metabolic syndrome and cardiovascular disease than obese women. The hypothalamus regulates a wide variety of homeostatic processes, including food intake and energy expenditure, which are tightly regulated in order to maintain proper energy homeostasis. Genetic causes of obesity are largely hypothalamic in origin, however obesity is multifactorial, consisting of both genetic and environmental components that contribute to the steadfast increase in its prevalence. In addition, the hypothalamus regulates the pituitary gland, an endocrine organ that is responsible for the synthesis and secretion of hormones that are important in the regulation of basal metabolism, reproduction and stress, all of which are dysregulated in obese patients. This work aims to elucidate genetic and environmental causes in hypothalamic and pituitary dysfunction in obesity. Our studies identified a new genetic target, fragile X messenger ribonucleoprotein 1 (FMR1) in the regulation of energy expenditure in the hypothalamus and etiology of FMR1-linked obesity in mice. We proposed that FMR1 is critical in the regulation of pro-opiomelanocortin (POMC) neuron function in the regulation of food-foraging locomotor activity. We also investigated the effects of diet-induced obesity, as diet is a main environmental factor in obesity, in pituitary gland homeostasis. We determined that diet-induced obesity alters pituitary plasticity, primarily in somatotrope and lactotrope populations that secrete growth hormone (GH) and prolactin, respectively, altering downstream hormone production. In a separate study, we investigated sex differences in diet-induced obesity pathogenesis and demonstrated that macrophage secreted protein, resistin-like molecule alpha (RELMɑ), critically protects females against diet-induced obesity. Collectively, these studies implicate a new genetic target in hypothalamic regulation of energy homeostasis and that diet-induced obesity alters pituitary plasticity and hormone production, which could explain endocrine dysfunction in obesity.