FGF21 acts in the brain to drive macronutrient-specific changes in behavioral motivation and brain reward signaling

Khan, Md Shahjalal H.; Kim, Sora Q.; Ross, Robert C.; Corpodean, Florina; Spann, Redin A.; Albarado, Diana A.; Fernandez-Kim, Sun O.; Clarke, Blaise; Berthoud, Hans-Rudolf; Münzberg, Heike; McDougal, David H.; He, Yanlin; Yu, Sangho; Albaugh, Vance L.; Soto, Paul L.; Morrison, Christopher D.

doi:10.1016/j.molmet.2024.102068

Molecular Metabolism

2025

DOI: 10.1016/j.molmet.2024.102068

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FGF21 acts in the brain to drive macronutrient-specific changes in behavioral motivation and brain reward signaling

Md Shahjalal H. Khan,

Sora Q. Kim,

Robert C. Ross

et al.

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Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency

Tiwari,

Jin,

Sun

et al. 2024

Preprint

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Citrin Deficiency (CD) is caused by inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. We discovered that SLC25A13 loss causes accumulation of glycerol-3-phosphate (G3P), which activates carbohydrate response element binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol, and to transcribe key genes ofde novolipogenesis. Mouse and human data establish G3P-ChREBP as a new mechanistic component of the Randle Cycle that contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) and forms part of a system that communicates metabolic states from liver to brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs, and drug candidates for both lean MASLD and support of urea cycle function in CD.

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Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency

Tiwari,

Jin,

Sun

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

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FGF21 acts in the brain to drive macronutrient-specific changes in behavioral motivation and brain reward signaling

Cited by 1 publication

References 64 publications

Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency

Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency

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