FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit

Flippo, Kyle H.; Trammell, Samuel A.J.; Gillum, Matthew P.; Aklan, İltan; Perez, Misty B; Yavuz, Yavuz; Smith, Nicholas K.; Jensen-Cody, Sharon O.; Zhou, Bolu; Claflin, Kristin E.; Beierschmitt, Amy; Fink‐Jensen, Anders; Knop, Filip K.; Palmour, Roberta M.; Grueter, Brad A.; Atasoy, Deniz; Potthoff, Matthew J.

doi:10.1016/j.cmet.2021.12.024

Cited by 44 publications

(51 citation statements)

References 54 publications

(78 reference statements)

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“…In fact, the human KLB gene is associated with alcohol intake, and Klb deletion in mice can increase alcohol preference (Schumann et al., 2016; Talukdar et al., 2016). This is consistent with work demonstrating that FGF21 can suppress alcohol intake in mice (Schumann et al., 2016; Søberg et al., 2018; Talukdar et al., 2016; Flippo et al, 2022). Therefore, the amygdala may be a target site for FGF21 activity that reinforces alcohol aversion.…”

Section: Discussionsupporting

confidence: 89%

Spatial distribution of beta‐klotho mRNA in the mouse hypothalamus, hippocampal region, subiculum, and amygdala

Bono

Miller

et al. 2022

J of Comparative Neurology

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Beta‐klotho (KLB) is a coreceptor required for endocrine fibroblast growth factor (FGF) 15/19 and FGF21 signaling in the brain. Klb is prominent within the hypothalamus, which is consistent with its metabolic functions, but diverse roles for Klb are now emerging. Central Klb expression is low but discrete and may govern FGF‐targeted sites. However, given its low expression, it is unclear if Klb mRNA is more widespread. We performed in situ hybridization to label Klb mRNA to generate spatial maps capturing the distribution and levels of Klb within the mouse hypothalamus, hippocampal region, subiculum, and amygdala. Semiquantitative analysis revealed that Klb‐labeled cells may express low, medium, or high levels of Klb mRNA. Hypothalamic Klb hybridization was heterogeneous and varied rostrocaudally within the same region. Most Klb‐labeled cells were found in the lateral hypothalamic zone, but the periventricular hypothalamic region, including the suprachiasmatic nucleus, contained the greatest proportion of cells expressing medium or high Klb levels. We also found heterogeneous Klb hybridization in the amygdala and subiculum, where Klb was especially distinct within the central amygdalar nucleus and ventral subiculum, respectively. By contrast, Klb‐labeled cells in the hippocampal region only expressed low levels of Klb and were typically found in the pyramidal layer of Ammon's horn or dentate gyrus. The Klb‐labeled regions identified in this study are consistent with reported roles of Klb in metabolism, taste preference, and neuroprotection. However, additional identified sites, including within the hypothalamus and amygdala, may suggest novel roles for FGF15/19 or FGF21 signaling.

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Section: Discussionsupporting

confidence: 89%

Spatial distribution of beta‐klotho mRNA in the mouse hypothalamus, hippocampal region, subiculum, and amygdala

Bono

Miller

et al. 2022

J of Comparative Neurology

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“…This “ NEFA-PPAR-FGF21-LPL ” axis is particularly intriguing in light of thinking that obesity and related diseases may represent an “FGF21-resistant” state analogous to insulin resistance [ 92 , 93 , 94 , 95 ] and with paradoxically high FGF21, and could operate alongside promising efforts to develop FGF21-directed therapy to treat atherogenic dyslipidemia, diabetes, and NAFLD [ 96 , 97 ]. Exploring FGF21 dynamics, as well as the FGF21/FGF1 ratio that has been proposed to regulate lipolysis [ 98 , 99 ] (and even the possible impact of FGF21 on carbohydrate and sugar taste preferences [ 100 ] and alcohol consumption [ 101 ]), in LMHR as part of the LEM, could provide insight into hormonal mechanisms of metabolic disease.…”

Section: Lipoprotein Lipase Regulatorsmentioning

confidence: 99%

The Lipid Energy Model: Reimagining Lipoprotein Function in the Context of Carbohydrate-Restricted Diets

Norwitz

Soto-Mota

Kaplan³

et al. 2022

Metabolites

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When lean people adopt carbohydrate-restricted diets (CRDs), they may develop a lipid profile consisting of elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs). The magnitude of this lipid profile correlates with BMI such that those with lower BMI exhibit larger increases in both LDL-C and HDL-C. The inverse association between BMI and LDL-C and HDL-C change on CRD contributed to the discovery of a subset of individuals—termed Lean Mass Hyper-Responders (LMHR)—who, despite normal pre-diet LDL-C, as compared to non-LMHR (mean levels of 148 and 145 mg/dL, respectively), exhibited a pronounced hyperlipidemic response to a CRD, with mean LDL-C and HDL-C levels increasing to 320 and 99 mg/dL, respectively, in the context of mean TG of 47 mg/dL. In some LMHR, LDL-C levels may be in excess of 500 mg/dL, again, with relatively normal pre-diet LDL-C and absent of genetic findings indicative of familial hypercholesterolemia in those who have been tested. The Lipid Energy Model (LEM) attempts to explain this metabolic phenomenon by positing that, with carbohydrate restriction in lean persons, the increased dependence on fat as a metabolic substrate drives increased hepatic secretion and peripheral uptake of TG contained within very low-density lipoproteins (VLDL) by lipoprotein lipase, resulting in marked elevations of LDL-C and HDL-C, and low TG. Herein, we review the core features of the LEM. We review several existing lines of evidence supporting the model and suggest ways to test the model’s predictions.

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“…To address these gaps, Flippo and colleagues 1 investigated the effects of FGF21 and a long-acting FGF21 analog (PF-05231023) on alcohol consumption in rodents and non-human primates. They first showed that in mice, alcohol consumption increased circulating FGF21 levels, selective FGF21 deletion from the liver increased alcohol use, and intraperitoneal administration of recombinant human FGF21 dose-dependently reduced alcohol consumption.…”

Section: Main Textmentioning

confidence: 99%

“…Further, the authors showed that KLB deletion in the BLA blocked FGF21's ability to suppress alcohol consumption, highlighting the necessity of FGF21 signaling in the BLA for alcoholrelated effects. Of note, previous studies found KLB expression in other brain regions, including the suprachiasmatic nucleus, nucleus solitary tract, and the hypothalamus, 6 to be involved in feeding and metabolic functions of FGF21, while BLA appears to play a key role in FGF21's effects on alcohol seeking behaviors (e.g., deletion of KLB in the BLA had no effect on FGF21's ability to suppress sucrose intake 1 ).…”

mentioning

confidence: 91%

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FGF21 regulates alcohol intake: New hopes on the rise for alcohol use disorder treatment?

Wang

Farokhnia

Leggio

2022

Cell Reports Medicine

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FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit

Cited by 44 publications

References 54 publications

Spatial distribution of beta‐klotho mRNA in the mouse hypothalamus, hippocampal region, subiculum, and amygdala

Spatial distribution of beta‐klotho mRNA in the mouse hypothalamus, hippocampal region, subiculum, and amygdala

The Lipid Energy Model: Reimagining Lipoprotein Function in the Context of Carbohydrate-Restricted Diets

FGF21 regulates alcohol intake: New hopes on the rise for alcohol use disorder treatment?

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