Altered Circadian Feeding Behavior and Improvement of Metabolic Syndrome in Obese Tac1-Deficient Mice

Abstract

BACKGROUND Metabolic function is regulated by the interplay of central and peripheral factors that ultimately regulate food intake and energy expenditure. The tachykinin substance P (SP) has been identified as a novel regulator of energy balance, however, the mechanisms underlying this effect are ill-defined and conflicting data regarding the role of SP on food intake have been reported by different groups.

OBJECTIVE To further characterize the metabolic role of the Tac1 gene products (SP and neurokinin A (NKA)) in mice through a series of genetic, metabolic and behavioral studies in Tac1 deficient mice.

RESULTS Tac1−/− mice are leaner than controls and display reduced food intake and altered feeding circadian rhythm, supported by disrupted expression of the clock genes Cry1/2, Per1/2 in the suprachiasmatic nucleus (SCN), medio-basal hypothalamus (MBH) and liver, as well as increased Pomc expression in the MBH. Tac1 ablation induced resistance to obesity, improved glucose tolerance, prevented insulin resistance under high-fat-diet, increased activation of brown adipose tissue and improved hepatic steatosis. Moreover, deletion of Tac1 in ob/ob mice ameliorated BW gain in females only but was sufficient to decrease fat and triglyceride content in the liver of males.

CONCLUSIONS These results provide further evidence that Tac1 controls circadian feeding behavior and metabolism in mice through mechanisms that involve the regulation of the melanocortin system. In addition, these studies suggest that the blockade of SP may offer a new method to treat metabolic syndrome.