AMPK alpha 2 in Kiss1 Neurons Is Required for Reproductive Adaptations to Acute Metabolic Challenges in Adult Female Mice

摘要

Atemporary and reversible inhibition of the hypothalamo-pituitary-gonadal axis is adaptive when energy reserves are diminished, allowing individual survival and energy accumulation for eventual reproduction. The AMP-activated protein kinase (AMPK) works as a cellular sensor of the AMP to ATP ratio and ultimately of energy availability. Activation of AMPK suppresses ATP-consuming processes and stimulates ATP-producing pathways. The AMPK alpha 2 catalytic subunit is expressed in multiple hypothalamic nuclei including those associated with reproductive control, ie, the anteroventral periventricular nucleus and the arcuate nucleus. Subsets of kisspeptin neurons in the anteroventral periventricular nucleus (20% in females) and arcuate nucleus (45% in males and 65% in females) coexpress AMPK alpha 2 mRNA. Using the Cre-loxP approach, we assessed whether AMPK alpha 2 in Kiss1 cells is required for body weight and reproductive function. The AMPK alpha 2-deleted mice show no difference in body weight and time for sexual maturation compared with controls. Males and females are fertile and have normal litter size. The AMPK alpha 2-deleted and control females have similar estradiol feedback responses and show no difference in Kiss1 mRNA expression after ovariectomy or ovariectomy plus estradiol replacement. In males, acute fasting decreased Kiss1 mRNA expression in both groups, but no effect was observed in females. However, after an acute fasting, control mice displayed prolonged diestrous phase, but AMPK alpha 2-deleted females showed no disruption of estrous cycles. Our findings demonstrate that the AMPK alpha 2 catalytic subunit in Kiss1 cells is dispensable for body weight and reproductive function in mice but is necessary for the reproductive adaptations to conditions of acute metabolic distress.