Lipids engage a kidney-brain GDF15 axisto suppress food intake

Growth differentiation factor 15 (GDF15) is an anorectic and weight-loss inducing hormone that responds to stimuli like endoplasmic reticulum stress, exercise, metformin and more recently dietary lipids. Given its potential as an anti-obesogenic agent, we examined how endogenous GDF15 responds to Intralipid infusion in different organs to regulate food intake in vivo. We found that acute Intralipid infusion into the upper small intestine (USI) inhibited food intake and increased plasma GDF15, as well as kidney and hepatic Gdf15 expression in chow-fed but not high-fat (HF)-induced hyperphagic male rats. Kidney Gdf15 knockdown blunted Intralipid-induced increases in kidney and plasma GDF15 levels as well as its feeding-lowering effects, while hepatic Gdf15 expression remained unaffected. Lastly, we knocked down GDNF family receptor α-like (Gfral) in the area postrema, which negated the feeding-lowering effect of Intralipid despite a rise in plasma GDF15 levels in chow rats. In summary, for the first time to our knowledge, we report that kidney GDF15 is necessary for USI intralipid sensing to trigger an area postrema axis to inhibit food intake. We propose that HF feeding impairs acute lipid sensing to lower feeding by negating the lipid-regulatory effect on kidney GDF15.