Understanding the Regulation of Energy Balance and Glucose Homeostasis, and the Etiology of Obesity and Type 2 Diabetes

Our research focuses on elucidating the function of the central melanocortin system in adaptive regulation of food intake, energy expenditure, and hepatic lipid metabolism in response to physiological and environmental conditions, such as food restriction, consumption of energy-dense diets and aging.

We have elucidated signaling mechanisms by which Proopiomelanocortin and Agouti-related protein-expressing neurons integrate diverse metabolic signals, such as leptin, insulin and glucocorticoids, and how disruption of these signaling mechanisms contributes to the development of metabolic disorders. In addition, we have identified a critical role for hypothalamic Agouti-related protein in regulation of hepatic lipid and cholesterol metabolism, as well as dietary preference in mice and humans. We also delineated mechanisms underlying hypothalamic neuronal repair, neurodegeneration and metabolic impairment in aging. Our recent endeavor is to elucidate novel mechanisms by which the brain senses metabolic and nutritional signals and to identify downstream effectors of the central melanocortinergic neurons. Together, these research efforts will help better understand how energy balance are regulated normally and how these regulations are disrupted in obesity, diabetes and aging.

Olofsson LE, Unger EK, Cheung CC, Xu AW. Modulation of AgRP neuronal function by Socs3 as an initiating event in diet-induced hypothalamic leptin resistance. Proc Natl Acad Sci U S A. 2013. 110(8):E697-706.      

Yulyaningsih E, Rudenko IA, Valdearcos M, Dahlén E, Vagena E, Chan A, Alvarez-Buylla A, Vaisse C, Koliwad SK, Xu AW. Acute lesioning and rapid repair of hypothalamic neurons outside the blood-brain barrier. Cell Rep. 2017. 19(11): 2257-2271.

Maier MT, Vilhelmsson A, Louie SM, Vagena E, Nomura DK, Koliwad SK, Xu AW. Regulation of hepatic lipid accumulation and distribution by Agouti-regulated protein. Endocrinology. 2018. 159(6): 2408-2420.

Nelson NG, Wu L, Maier MT, Lam D, Cheang R, Alba D, Huang A, Neumann DA, Hill T, Vagena E, Barsh GS, Medina MW, Krauss RM, Koliwad SK, Xu AW. A gene-diet interaction controlling relative intake of dietary carbohydrates and fats. Mol Metab, 2022. 58: 101442.

Vagena E, Crneta J, Engstrom P, He L, Yulyaningsih E, Korpel NL, Cheang RT, Bachor TP, Huang A, Michel G, Attal K, Berrios DI, Valdearcos M, Koliwad SK, Olsen DP, Yi CX, Xu AW. ASB4 modulates central melanocortinergic neurons and calcitonin signaling to control satiety and glucose homeostasis. Sci Signal. 2022. 15 (733): eabj8204. Epub 2022 May 10.