Identifying metabolic mechanisms that regulate appetite and foodintake

Information

  • Research Project
  • 10309083
  • ApplicationId
    10309083
  • Core Project Number
    R21AG071436
  • Full Project Number
    1R21AG071436-01A1
  • Serial Number
    071436
  • FOA Number
    PA-20-195
  • Sub Project Id
  • Project Start Date
    9/1/2021 - 2 years ago
  • Project End Date
    5/31/2023 - a year ago
  • Program Officer Name
    FRIDELL, YIH-WOEI
  • Budget Start Date
    9/1/2021 - 2 years ago
  • Budget End Date
    5/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    8/25/2021 - 2 years ago

Identifying metabolic mechanisms that regulate appetite and foodintake

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.

IC Name
NATIONAL INSTITUTE ON AGING
  • Activity
    R21
  • Administering IC
    AG
  • Application Type
    1
  • Direct Cost Amount
    125000
  • Indirect Cost Amount
    86250
  • Total Cost
    211250
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    866
  • Ed Inst. Type
  • Funding ICs
    NIA:211250\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    CMAD
  • Study Section Name
    Cellular Mechanisms in Aging and Development Study Section
  • Organization Name
    JOSLIN DIABETES CENTER
  • Organization Department
  • Organization DUNS
    071723084
  • Organization City
    BOSTON
  • Organization State
    MA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    022155306
  • Organization District
    UNITED STATES