Endocrine hormones released by peripheral tissues, such as adipose tissue, skeletal muscle and the liver, play an important role in metabolic crosstalk and homeostasis and contribute to disease pathogenesis. We recently identified Tsukushi (TSK) as a liver-enriched secreted factor that is highly inducible in response to increased energy expenditure. TSK null mice were resistant to diet-induced obesity, insulin resistance, and diet-induced NASH as a result of enhanced sympathetic activation and brown fat thermogenesis. However, the mechanisms underlying TSK action remain incompletely elucidated. Melanocortin 4 receptor (MC4R) is a key regulator of energy balance and its mutations represent the most common monogenic cause of obesity in human. In this study, we generated TSK/MC4R double knockout mice to explore potential crosstalk between the TSK and MC4R signaling pathways. While MC4R-null mice developed severe obesity when fed standard rodent chow, TSK inactivation nearly completely abolished the defects of energy balance caused by MC4R deficiency. Remarkably, ablation of TSK normalized food intake and corrected hepatic steatosis, adipose tissue inflammation, and insulin resistance in MC4R null mice. TSK deficiency also rescued the impairments of thermogenic gene expression caused by MC4R deficiency. Those results suggest that TSK likely acts downstream or in parallel to MC4R signaling to regulate feeding behavior and energy expenditure. Our work supports a rationale for therapeutic blockade of TSK for the treatment of obesity and metabolic disease caused by MC4R mutations.
Q. Wang: None. J. Lin: None.
National Institutes of Health (DK102456, AG055379, DK114220)