FGF21 Mediates the Thermogenic and Insulin-Sensitizing Effects of Dietary Methionine Restriction but Not Its Effects on Hepatic Lipid Metabolism

Wanders, Desiree; Forney, Laura A.; Stone, Kirsten P.; Burk, David H.; Pierse, Alicia; Gettys, Thomas W.

doi:10.2337/db16-1212

Cited by 118 publications

(197 citation statements)

References 57 publications

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“…1B) mice consuming the MD diet showed a significant improvement in glucose tolerance, and male mice had lower fasting blood glucose. As MR promotes insulin sensitivity in the liver and skeletal muscle (9, 15), we performed insulin and pyruvate tolerance tests over the following 3 wk. We observed a significant improvement in both insulin sensitivity (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The metabolic chamber data suggest that the weight loss following MD is most likely due to increased energy expenditure. We determined that Fgf21, a liver‐derived hormone that regulates energy balance and is induced by MR (9), is induced at the transcriptional level in mice of both sexes fed a WD MD diet, as compared to mice on a WD AA diet (Fig. 3F).…”

Section: Resultsmentioning

confidence: 99%

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Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

Yang

Miller

et al. 2018

FASEB j.

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Obesity and diabetes are major challenges to global health, and there is an urgent need for interventions that promote weight loss. Dietary restriction of methionine promotes leanness and improves metabolic health in mice and humans. However, poor long-term adherence to this diet limits its translational potential. In this study, we develop a short-term methionine deprivation (MD) regimen that preferentially reduces fat mass, restoring normal body weight and glycemic control to diet-induced obese mice of both sexes. The benefits of MD do not accrue from calorie restriction, but instead result from increased energy expenditure. MD promotes increased energy expenditure in a sex-specific manner, inducing the fibroblast growth factor (Fgf)-21-uncoupling protein (Ucp)-1 axis only in males. Methionine is an agonist of the protein kinase mechanistic target of rapamycin complex (mTORC)-1, which has been proposed to play a key role in the metabolic response to amino acid-restricted diets. In our study, we used a mouse model of constitutive hepatic mTORC1 activity and demonstrate that suppression of hepatic mTORC1 signaling is not required for the metabolic effects of MD. Our study sheds new light on the mechanisms by which dietary methionine regulates metabolic health and demonstrates the translational potential of MD for the treatment of obesity and type 2 diabetes.-Yu, D., Yang, S. E., Miller, B. R., Wisinski, J. A., Sherman, D. S., Brinkman, J. A., Tomasiewicz, J. L., Cummings, N. E., Kimple, M. E., Cryns, V. L., Lamming, D. W. Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

Yang

Miller

et al. 2018

FASEB j.

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“…The answer is probably yes, based on recent work in which mice were initially fed high‐fat diets to produce obesity, followed by 8 weeks of dietary MR . MR reduced BW from 44 g to 27 g and adiposity from 32% to 17% over the 8‐week study . These findings argue that dietary MR would be effective in producing weight loss in the context of obesity and weight stability in individuals without obesity.…”

Section: Discussionmentioning

confidence: 99%

The Components of Age‐Dependent Effects of Dietary Methionine Restriction on Energy Balance in Rats

Wanders

Forney

Stone

et al. 2018

Obesity

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ObjectiveDietary methionine restriction (MR) improves biomarkers of metabolic health, in part through coordinated increases in energy intake and energy expenditure (EE). Some metabolic benefits of dietary MR are secondary to its effects on energy balance so this study’s purpose was to examine how age at initiation of MR influences its effects on energy balance and body composition.MethodsEnergy balance was examined in rats provided Control or MR diets for 9 months after weaning or in rats between 6 and 12 months of age.ResultsRats provided the Control diet for 9 months after weaning increased their body weight (BW) and fat mass by 5- and 8-fold, respectively, while BW and fat accumulation were reduced to 50% of Controls in the MR group. In adult rats fed the respective diets between 6 and 12 months of age, dietary MR increased energy intake by ~23% but the 15% increase in EE was sufficient to prevent increases in BW or fat mass.ConclusionsDietary MR produces comparable increases in EE in young, growing animals and in mature animals, but young animals continue to deposit new tissue because of the proportionately larger effect of MR on energy intake relative to maintenance requirements.

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“…Many anti-diabetic drugs also increase serum levels of FGF21, which may mediate some of their beneficial effects [30]. Another stimulus for the hepatic expression of FGF21 is deprivation of amino acids, such as methionine, by a protein-poor diet [31]. …”

Section: Synthesis and Functionsmentioning

confidence: 99%

Fibroblast growth factor 21 in chronic kidney disease

et al. 2018

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Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF family that acts as a metabolic regulator of both glucose and lipid metabolism. Similar to fibroblast growth factor 23 (FGF23), serum FGF21 levels rise progressively with the loss of renal function, reaching 20 times normal values in end-stage renal disease. In patients with chronic kidney disease (CKD), higher serum FGF21 levels correlate with poorer metabolic profile, higher inflammatory markers, more comorbidities, and higher mortality. The high serum FGF21 levels are above and beyond what can be explained by the loss of FGF21 renal clearance, suggesting increased production and/or impaired non-renal clearance. In diabetic nephropathy, serum FGF21 levels correlate with the severity of albuminuria and faster loss of glomerular filtrate rate and can potentially be a biomarker of poor prognostic. The observational and associative human data contrast sharply with in vitro and in vivo preclinical experimental data, which is more in line with a protective role of FGF21 in chronic nephropathies. We here review the physiology of FGF21, and the literature regarding its behavior in CKD with particular focus on diabetic nephropathy. Finally, we speculate on the role of FGF21 in CKD.

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FGF21 Mediates the Thermogenic and Insulin-Sensitizing Effects of Dietary Methionine Restriction but Not Its Effects on Hepatic Lipid Metabolism

Cited by 118 publications

References 57 publications

Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

The Components of Age‐Dependent Effects of Dietary Methionine Restriction on Energy Balance in Rats

Fibroblast growth factor 21 in chronic kidney disease

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