FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake

Jensen-Cody, Sharon O.; Flippo, Kyle H.; Claflin, Kristin E.; Yavuz, Yavuz; Sapouckey, Sarah A.; Walters, Grant C.; Usachev, Yuriy M.; Atasoy, Deniz; Gillum, Matthew P.; Potthoff, Matthew J.

doi:10.1016/j.cmet.2020.06.008

Cited by 102 publications

(129 citation statements)

References 72 publications

Supporting

Mentioning

125

Contrasting

Order By: Relevance

“…We demonstrate that FGF21 signaling specifically to glutamatergic, but not GABAergic, neurons is required for the increases in energy expenditure and weight loss associated with low protein diet consumption. A requirement for FGF21 signaling to glutamatergic neurons in the ventromedial hypothalamus (VMH) was also recently demonstrated for its ability to regulate sugar intake 30 . However, in that same study FGF21 signaling to neurons in the VMH was not required for FGF21-mediated protection against weight gain 30 .…”

Section: Discussionmentioning

confidence: 97%

“…A requirement for FGF21 signaling to glutamatergic neurons in the ventromedial hypothalamus (VMH) was also recently demonstrated for its ability to regulate sugar intake 30 . However, in that same study FGF21 signaling to neurons in the VMH was not required for FGF21-mediated protection against weight gain 30 . Thus, together these data suggest that FGF21 regulates sugar consumption and body weight through spatially distinct populations of KLB + glutamatergic neurons.…”

Section: Discussionmentioning

confidence: 97%

“…FGF21 signaling to KLB-expressing cells in the central nervous system (CNS) is required for the protection against weight gain attributed to dietary protein restriction 16 . Our recent work indicates FGF21 signals directly to KLB-expressing glutamatergic neurons to suppress carbohydrate intake 30 . However, it has yet to be investigated what types of neurons FGF21 signals to in order to elicit the Figure 2.…”

Section: Fgf21 Does Not Influence Protein Preference Either Alone or mentioning

confidence: 96%

See 2 more Smart Citations

FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution

Flippo

Jensen-Cody

Claflin

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Alterations in macronutrient intake can have profound effects on energy intake and whole-body metabolism. For example, reducing protein intake increases energy expenditure, increases insulin sensitivity and decreases body weight in rodents. Fibroblast growth factor 21 (FGF21) signaling in the brain is necessary for the metabolic effects of dietary protein restriction and has more recently been proposed to promote protein preference. However, the neuron populations through which FGF21 elicits these effects are unknown. Here, we demonstrate that deletion of β-klotho in glutamatergic, but not GABAergic, neurons abrogated the effects of dietary protein restriction on reducing body weight, but not on improving insulin sensitivity in both diet-induced obese and lean mice. Specifically, FGF21 signaling in glutamatergic neurons is necessary for protection against body weight gain and induction of UCP1 in adipose tissues associated with dietary protein restriction. However, β-klotho expression in glutamatergic neurons was dispensable for the effects of dietary protein restriction to increase insulin sensitivity. In addition, we report that FGF21 administration does not alter protein preference, but instead promotes the foraging of other macronutrients primarily by suppressing simple sugar consumption. This work provides important new insights into the neural substrates and mechanisms behind the endocrine control of metabolism during dietary protein dilution.

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: Fgf21 Does Not Influence Protein Preference Either Alone or mentioning

confidence: 96%

See 1 more Smart Citation

FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution

Flippo

Jensen-Cody

Claflin

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…FGF21 directly signals adipose tissue to improve insulin sensitivity [ 169 , 170 ], while it signals the CNS to increase energy expenditure and decrease body weight [ 169 , 171 , 172 ] ( Figure 2 ). Recent research demonstrated that FGF21 signaling to glutamatergic neurons lowers carbohydrate intake and non-nutritive sweet-taste preference in mice [ 173 ]. Interestingly, FGF21 signaling to the ventromedial hypothalamus (VMH) is required for its effects on lowering carbohydrate intake but not non-nutritive sweet-taste preference or body weight.…”

Section: Introductionmentioning

confidence: 99%

Hepatokines and metabolism: Deciphering communication from the liver

Jensen-Cody

Potthoff

2021

Molecular Metabolism

Self Cite

143

View full text Add to dashboard Cite

“…The increase in plasma FGF21 in response to PPARα stimulation has been suggested to be involved in a negative feedback loop to inhibit lipolysis ( 60 ). Hepatic FGF21 is also increased in response to high glucose via activation of Carbohydrate-response element-binding protein (ChREBP) ( 61 ) and FGF21 lowers the preference for glucose intake ( 62 ) by stimulation of glutamatergic neurons in the ventromedial hypothalamus (VMH) ( 63 ). Moreover, FGF21 facilitates glucose ( 64 ), lipid uptake ( 65 ) and adipogenesis in the adipose tissue ( 66 ), which prevent ectopic lipid accumulation in liver and skeletal muscle ( 67 ).…”

Section: Introductionmentioning

confidence: 99%

FGF19 and FGF21 for the Treatment of NASH—Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human

Henriksson

Andersen

2020

Front. Endocrinol.

View full text Add to dashboard Cite

FGF19 and FGF21 analogues are currently in clinical development for the potential treatment of NASH. In Phase 2 clinical trials analogues of FGF19 and FGF21 decrease hepatic steatosis with up to 70% (MRI-PDFF) after 12 weeks and as early as 12–16 weeks of treatment an improvement in NASH resolution and fibrosis has been observed. Therefore, this class of compounds is currently of great interest in the field of NASH. FGF19 and FGF21 belong to the endocrine FGF19 subfamily and both require the co-receptor beta-klotho for binding and signalling through the FGF receptors. FGF19 is expressed in the ileal enterocytes and is released into the enterohepatic circulation in response to bile acids stimuli and in the liver FGF19 inhibits hepatic bile acids synthesis by transcriptional regulation of Cyp7A1, which is the rate limiting enzyme. FGF21 is, on the other hand, highly expressed in the liver and is released in response to high glucose, high free-fatty acids and low amino-acid supply and regulates energy, glucose and lipid homeostasis by actions in the CNS and in the adipose tissue. FGF19 and FGF21 are differentially expressed, have distinct target tissues and separate physiological functions. It is therefore of peculiar interest to understand why treatment with both FGF19 and FGF21 analogues have strong beneficial effects on NASH parameters in mice and human and whether the mode of action is overlapping This review will highlight the physiological and pharmacological effects of FGF19 and FGF21. The potential mode of action behind the anti-steatotic, anti-inflammatory and anti-fibrotic effects of FGF19 and FGF21 will be discussed. Finally, development of drugs is always a risk benefit analysis and the human relevance of adverse effects observed in pre-clinical species as well as findings in humans will be discussed. The aim is to provide a comprehensive overview of the current understanding of this drug class for the potential treatment of NASH.

show abstract

FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake

Cited by 102 publications

References 72 publications

FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution

FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution

Hepatokines and metabolism: Deciphering communication from the liver

FGF19 and FGF21 for the Treatment of NASH—Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human

Contact Info

Product

Resources

About