TY - JOUR TI - A genetic variant of fatty acid amide hydrolase (FAAH) exacerbates hormone-mediated orexigenic feeding in mice AU - Balsevich, Georgia AU - Petrie, Gavin N AU - Heinz, Daniel E AU - Singh, Arashdeep AU - Aukema, Robert J AU - Hunker, Avery C AU - Vecchiarelli, Haley A AU - Yau, Hiulan AU - Sticht, Martin AU - Thompson, Roger J AU - Lee, Francis S AU - Zweifel, Larry S AU - Chelikani, Prasanth K AU - Gassen, Nils C AU - Hill, Matthew N A2 - Elmquist, Joel K A2 - Taffe, Michael A A2 - Patel, Sachin A2 - Chua, Streamson VL - 12 PY - 2023 DA - 2023/04/11 SP - e81919 C1 - eLife 2023;12:e81919 DO - 10.7554/eLife.81919 UR - https://doi.org/10.7554/eLife.81919 AB - Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide. A polymorphism in FAAH (FAAH C385A) reduces FAAH expression, increases anandamide levels, and increases the risk of obesity. Nevertheless, some studies have found no association between FAAH C385A and obesity. We investigated whether the environmental context governs the impact of FAAH C385A on metabolic outcomes. Using a C385A knock-in mouse model, we found that FAAH A/A mice are more susceptible to glucocorticoid-induced hyperphagia, weight gain, and activation of hypothalamic AMP-activated protein kinase (AMPK). AMPK inhibition occluded the amplified hyperphagic response to glucocorticoids in FAAH A/A mice. FAAH knockdown exclusively in agouti-related protein (AgRP) neurons mimicked the exaggerated feeding response of FAAH A/A mice to glucocorticoids. FAAH A/A mice likewise presented exaggerated orexigenic responses to ghrelin, while FAAH knockdown in AgRP neurons blunted leptin anorectic responses. Together, the FAAH A/A genotype amplifies orexigenic responses and decreases anorexigenic responses, providing a putative mechanism explaining the diverging human findings. KW - glucocorticoids KW - endocannabinoids KW - feeding KW - FAAH KW - obesity JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -