Deletion of the Feeding-Induced Hepatokine TSK Ameliorates the Melanocortin Obesity Syndrome

• DOI: 10.2337/db21-0161
• Publication Date: 2021-06-28T16:25:27Z
• Authors: Qiuyu Wang; Peng Zhang; Isin Cakir; Lin Mi; Roger D. Cone; Jiandie D. Lin
• Keywords: Energy homeostasis; Melanocortins; Homeostasis

Work in recent decades has established that metabolic hormones released by endocrine cells and diverse other cell types serve to regulate nutrient intake energy homeostasis. Tsukushi (TSK) is a leucine-rich repeat-containing protein secreted primarily the liver exerts an inhibitory effect on brown fat sympathetic innervation thermogenesis. Despite this, physiological regulation of TSK mechanisms underlying its effects balance remain poorly understood. Here we show hepatic expression plasma concentrations are induced feeding regulated melanocortin-4 receptor (MC4R) signaling. We generated MC4R–double-knockout mice elucidate nature cross talk between central regulatory circuit balance. Remarkably, inactivation restores balance, ameliorates hyperphagia, improves health MC4R-deficient mice. ablation enhances thermogenic gene fat, dampens obesity-association inflammation adipose tissue, protects MC4R-null from diet-induced nonalcoholic steatohepatitis. At cellular level, deficiency augments feeding-induced c-Fos paraventricular nucleus hypothalamus. These results illustrate maintaining