Calorie restriction and the peripherally-derived growth factor, FGF21, have been correlated with increased lifespan. The hypothalamus plays an important role in the adjustment of whole body metabolism in calorie restriction. We uncovered that cell-selective impairment of hypothalamic Agouti-related peptide (AgRP)- expressing neuronal circuitry, part of the hypothalamic melanocortin system, in ad libitum fed mice, results in accelerated aging phenotype of many tissues, including the immune system and bone. In addition, we found that males of mice strains with impaired AgRP neuronal circuitry have shorter mean life-span when ad libitum fed. Our central hypothesis is that the AgRP system functions as a flip-flop switch for of fuel utilization for all tissues, and, that proper adjustment in the functioning of this central pathway is key in the aging process. We will test our hypothesis through the following specific aims:
Aim 1. To test the hypothesis that calorie restriction-induced changes in the activity and synaptic input organization of the melanocortin system is mimicked by FGF21.
Aim 2. To unmask if hypothalamic AgRP neurons are critical for behavioral- and peripheral tissue adaptations to calorie restriction and FGF21.
Aim 3. To determine the role of the AgRP neurons in the effect of calorie restriction and FGF21 on hippocampal and cortical circuit integrity. Studies of this project will offer conceptual interface with Projects 1-3 as well as cellular- and behavioral analyzes for studies proposed in those projects.
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