Liver energy homeostasis impacts hypothalamus gene expression and food intake regulation

Abstract

Several neuronal populations within the hypothalamus are known to modulate feeding behavior in mammals. Specifically, the arcuate nucleus contains appetite‐suppressing neurons pro‐opiomelanocortin (POMC), and appetite‐stimulating neurons neuropeptide Y (NPY)/agouti‐related peptide (AgRP) neurons. These neurons receive peripheral signals through blood and peripheral vagal afferents fibers. However, it is not well understood how peripheral signals, such as liver energy metabolism, may impact these neuronal populations to modulate feeding behavior. Herein, we used a hepatocyte‐specific PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy homeostasis in the expression of arcuate nucleus genes involved in food intake regulation, and acute feeding behavior after peripheral delivery of nutrient or peripheral satiation hormones. To assess the impact of liver energy changes on arcuate nucleus gene expression, we used a fasting/refeeding paradigm (16‐hour fast, 2‐hour food withdrawal, and 16‐hour fast with a 4‐hour refeed). We observed reductions in liver PGC1a mRNA expression in LPGC1a compared to wildtype (WT) during all fasting and refed states. LPGC1a mice had significantly lower liver ATP and increased AMP during a fasted state. Suggesting that during a fasted state, the LPGC1a mice struggle to maintain liver energy homeostasis. Furthermore, LPGC1a mice had significantly increased AgRP mRNA expression in the hypothalamus during a fast. Interestingly, POMC expression was lower in LPGC1a mice at 2hrs and refed compared to WT and showed no change across any of the energy states. Importantly, acute food intake following 2 hr food withdrawal was not inhibited by intraperitoneal glucose or GLP‐1 in LPGC1a mice. Together these results suggest that a reduced liver energy state modulates activity of hypothalamic POMC and AgRP neurons, potentially contributing to alterations in feeding behavior of LPGC1a mice previously observed.