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

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posted on 28.06.2021, 15:40 by Qiuyu Wang, Peng Zhang, Isin Cakir, Lin Mi, Roger D. Cone, Jiandie D. Lin
Work in recent decades has established that metabolic hormones released by endocrine cells and diverse other cell types serve to regulate nutrient intake and energy homeostasis. Tsukushi (TSK) is a leucine-rich repeat-containing protein secreted primarily by the liver that exerts an inhibitory effect on brown fat sympathetic innervation and thermogenesis. Despite this, physiological regulation of TSK and the mechanisms underlying its effects on energy balance remain poorly understood. Here we show that hepatic expression and plasma concentrations of TSK are induced by feeding and regulated by melanocortin-4 receptor (MC4R) signaling. We generated TSK and MC4R double knockout mice to elucidate the nature of crosstalk between TSK and the central regulatory circuit of energy balance. Remarkably, TSK inactivation restores energy balance, ameliorates hyperphagia, and improves metabolic health in MC4R deficient mice. TSK ablation enhances thermogenic gene expression in brown fat, dampens obesity-association inflammation in the liver and adipose tissue, and protects MC4R null mice from diet-induced non-alcoholic steatohepatitis. At the cellular level, TSK deficiency augments feeding-induced c-Fos expression in paraventricular nucleus of hypothalamus. These results illustrate physiological crosstalk between TSK and the central regulatory circuit in maintaining energy balance and metabolic homeostasis.

Funding

This work was supported by NIH (DK118731 and DK102456, J.D.L.; DK070332, R.D.C.). We thank Dr. Liangyou Rui for providing technical and scientific advice. We thank the Michigan Diabetes Research Center and the Michigan Nutrition and Obesity Research Center (NIH grants P30-DK020572 and P30-DK089503) for supporting core services used in this study.

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