Endocrine Abstracts

Objectives: Overweight and obesity currently burden our public health, and especially with the aging process in the world, the incidence of obesity is significantly higher in women than that in men partly. Recent studies reported that hypothalamic kisspeptin neurons, with obvious changes of number and structure in female during life, play a crucial role in the regulation of central energy homeostasis. But the precise mechanism remains an enigma.

Methods: High-fat fed Kiss1-CreGFP female mice were used in this study. Selectively activated kisspeption neurons by using Designer-receptors-exclusively-activated-by-designer-drugs(DREADDs) technology and denervation of the sympathetic nerve in iBAT were used to demonstrate the mechanism by which ARC Kisspeptin neurons activate brown fat thermogenesis in female mice.

Results: The Kiss1-CreGFP female mice were injected with AAV-DIO-hM3D(Gq)-mCherry virus in ARC through Stereotactic injection. Three weeks later, AAV was successfully transfected and expressed the corresponding receptor, which were greatly activated by CNO, then the expression of neuronal activation marker c-fos was significantly enhanced. Selective activation of Kisspeptin neurons resulted in decreased body weight, improved glucose metabolism, increased energy expenditure, increased iBAT(brown adipose tissue), decreased sWAT, gWAT, rWAT (white adipose tissue) in female mice(P<0.05). The norepinephrine(NE) concentration, sympathetic specific indicator tyrosine hydroxylase (TH), the number of brown adipose cells and the expression of thermogenic related genes were significantly increased in activated group (P<0.05). The metabolic improvement effect disappeared in activating kisspeptin^ARC neurons after sympathetic nerve denervation of iBAT, and female mice gained weight, impaired glucose metabolism, failed activation of brown fat, and significantly decreased thermogenesis (P>0.05). But the control group of beneficial effects by chemogenetics activation on weight reduction, glucose metabolism improvement and brown fat thermogenesis activation still existed (P<0.05).

Conclusion: Chemogenetics can relatively specifically activate Kisspeptin neurons in the ARC of the hypothalamus in female mice, and the activated Kisspeptin has an effect on energy metabolism, mainly reduced weight, improved glucose metabolism, increased thermogenic and dissipative, increased brown adipose tissue, strengthened sympathetic activity innervating iBAT, and significantly improved high fat induced obesity. iBAT sympathetic denervation experiments confirmed that Kisspeptin^ARC neurons in female mice modulate iBAT activation through sympathetic nerve to improve systemic energy metabolism.

Keywords: Kisspeptin, Female, Sympathetic Nerve, BAT, Thermogenesis