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Fatty Acids Increase GDF15 and Reduce Food Intake Through a GFRAL Signaling Axis

Version 2 2024-04-17, 17:13
Version 1 2023-10-17, 21:04
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posted on 2024-04-17, 17:13 authored by Dongdong Wang, Maria Joy Therese Jabile, Junfeng Lu, Logan K. Townsend, Celina M. Valvano, Jaya Gautam, Battsetseg Batchuluun, Evangelia E. Tsakiridis, James S.V. Lally, Gregory R. Steinberg

Abstract: In contrast to the well-defined biological feedback loops controlling glucose, the mechanisms by which the body responds to changes in fatty acid availability are less clearly defined. GDF15 suppresses the consumption of diets high in fat but is paradoxically increased in obese mice fed a high-fat diet. Given this interrelationship, we investigated whether diets high in fat could directly increase GDF15 independently of obesity. We found that fatty acids increase GDF15 levels dose-dependently with the greatest response observed with linolenic acid. GDF15 mRNA expression was modestly increased in the gastrointestinal tract, however, kidney GDF15 mRNA was ~1000-fold higher and was increased by over 3-fold with subsequent RNAscope analysis showing elevated expression within the cortex and outer medulla. Treatment of wildtype mice with linolenic acid reduced food intake and body mass, however, this effect was disappeared in mice lacking the GDF15 receptor GFRAL. An equal caloric load of glucose did not suppress food intake or reduce body mass in either WT or GFRAL KO mice. These data indicate that fatty acids such as linolenic acid increases GDF15 and suppresses food intake through a mechanism requiring GFRAL. These data suggest that a primary physiological function of GDF15 may be as a fatty acid sensor designed to protect cells from fatty acid overload.


Article Highlights:

· The mechanisms by which the body responds to changes in fatty acid availability are less clearly defined.

· We investigated whether diets high in fat could directly increase GDF15 independently of obesity.

· Fatty acids increase GDF15 and reduce food intake through a GFRAL signaling axis.

· GDF15 is a sensor of fatty acids that may have important implications for explaining increased satiety following consumption of diets high in fat.

Funding

Government of Canada > Canadian Institutes of Health Research 201709FDN-CEBA-116200

Diabetes Canada Investigator Award x DI-5-17-5302-GS

J. Bruce Duncan Endowed Chair in Metabolic Diseases

McMaster Institute for Research on Aging (MIRA)

Michael DeGroote Fellowship Award in Basic Biomedical Science

Tier 1 Canada Research Chair in Metabolic Diseases

CIHR Post-Doctoral Fellowship Award

History

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