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Download fileDeletion of the Feeding-Induced Hepatokine TSK Ameliorates the Melanocortin Obesity Syndrome
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posted on 2021-06-28, 15:40 authored by Qiuyu Wang, Peng Zhang, Isin Cakir, Lin Mi, Roger D. Cone, Jiandie D. LinWork 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.