Identifying metabolic mechanisms that regulate appetite and foodintake

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Project Summary Understanding how appetite and food consumption are regulated is critical to the aging field. From an innovative high-throughput C. elegans screen of transcription factors, in which we identified regulators of food consumption (here termed feeding), we determined that feeding is dramatically reduced by knockdown of crh-1 (CREB), which is inhibited by AMP-activated protein kinase (AMPK). AMPK is a key sensor of low energy states that inhibits growth signals and promotes catabolic processes and is of great interest in the aging field. Our exciting preliminary findings indicate that AMPK and certain other metabolic signals regulate feeding in unexpected ways and have revealed a new behavior pattern that is a major regulator of feeding. They suggest that: (1) In C. elegans AMPK signals “hunger” by acting in multiple tissues and in part by inhibiting CRH-1. AMPK thereby induces the animal to dwell on food (“eating”) but also to perceive that this food is inadequate, so that when possible it will leave in search of better food, paradoxically reducing food consumption. (2) This food-leaving behavior, which we term metabolic food aversion, is also triggered by other states of perceived nutritional inadequacy, including lack of the mono-unsaturated fatty acid (MUFA) oleic acid (OA) or other specific FAs. (3) In most but not all cases metabolic food aversion can be averted by OA supplementation, suggesting that an OA-derived lipid signal indicates satiety or corrects certain metabolic imbalances. (4) Like food dwelling, metabolic food aversion depends upon serotonin signaling, but is related to a behavior whereby C. elegans avoids food that it perceives to be pathogenic. In this exploratory project we will test and extend these intriguing models through two Aims. In Aim 1 we will identify signals that mediate AMPK/CRH-1-regulated hunger behaviors. We will explore how AMPK and CRH-1 expression in different tissues influences feeding and investigate the involvement of well- characterized serotonin-mediated, food-induced, and other signals in their regulation of food dwelling and aversion. In Aim 2, we will leverage targeted screening and follow-up analyses to elucidate metabolic mechanisms that regulate food aversion and dwelling. We will complete a medium-scale gene knockdown screen to identify metabolic perturbations that induce aversion that is or is not suppressible by OA. We will investigate whether aversion is generally paired with increased food dwelling and is dependent upon signaling mechanisms identified in Aim 1, as is true for the AMPK/CRH-1 pathway. Finally, we will ask whether some aversion events signal through AMPK and begin to identify tissues from which aversion signals originate. This project will identify mechanisms that link metabolic deficits to specific feeding behaviors: food dwelling and seeking of higher quality food, providing fundamental biological insights at a level of clarity that would be possible only in C. elegans.