FGF21 is an endocrine signal of protein restriction

Laeger, Thomas; Henagan, Tara M.; Albarado, Diana C.; Redman, Leanne M.; Bray, George A.; Noland, Robert C.; Münzberg, Heike; Hutson, Susan M.; Gettys, Thomas W.; Schwartz, Michael W.; Morrison, Christopher D.

doi:10.1172/jci74915

Cited by 464 publications

(631 citation statements)

References 59 publications

Supporting

Mentioning

565

Contrasting

Unclassified

Order By: Relevance

“…Additionally, the increased levels of FGF21 may be related to LPD-induced metabolic improvement. Laeger et al demonstrated that serum levels of FGF21 specifically increased on exposure to an LPD, regardless of overall calorie intake, in both rodents and humans [40]. FGF21 exerts beneficial effects on energy metabolism, such as increasing glucose uptake into adipose tissue and lowering body weight through increased energy expenditure [41].…”

Section: Discussionmentioning

confidence: 99%

A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity

et al. 2016

View full text Add to dashboard Cite

Aims/hypothesis The efficacy of a low-protein diet (LPD) on diabetic nephropathy is controversial. We aimed to investigate the renoprotective effects of an LPD and the underlying molecular mechanism in a rat model of type 2 diabetes and obesity. Methods Diabetic male Wistar fatty (fa/fa) rats (WFRs) were treated with a standard diet (23.84% protein) or an LPD (5.77% protein) for 20 weeks from 24 weeks of age. We investigated the effect of the LPD on renal function, fibrosis, tubular cell damage, inflammation, mitochondrial morphology of proximal tubular cells (PTCs), apoptosis, autophagy and activation of mammalian target of rapamycin complex 1 (mTORC1). Results Kidney weight, albuminuria, excretion of urinary liver-type fatty acid binding protein, levels of plasma cystatin C and changes in renal histology, including fibrosis, tubular cell damage and inflammation, were aggravated in WFRs compared with non-diabetic Wistar lean rats (WLRs). Fragmented and swelling mitochondria accumulated in PTCs and apoptosis were enhanced in the kidney of WFRs. Immunohistochemical staining of p62 and p-S6 ribosomal protein (p-S6RP) in the tubular lesions of WFRs was increased compared with WLRs. The LPD intervention clearly ameliorated damage as shown by the assessment of renal function and histology, particularly tubulointerstitial damage in diabetic kidneys. Additionally, the 5.77% LPD, but not the 11.46% LPD, significantly suppressed p-S6RP levels and increased microtubule-associated protein light chain 3-II levels in the renal cortex. The LPD intervention partially decreased HbA 1c levels in WFRs, and no differences in mean BP were observed among any of the groups. Conclusions/interpretation A very-low-protein diet improved advanced diabetic renal injuries, including tubulointerstitial damage, by restoring autophagy through the suppression of the mTORC1 pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The metabolic response to protein restriction is similar to that observed under leucine or methionine restriction [7]. Serum levels of FGF21 increase in both rodents and humans upon exposure to LPDs, regardless of overall caloric intake [105,106].…”

Section: Amino Acid-deficient and Low-protein Diets Increase Energy Ementioning

confidence: 96%

“…Protein restriction is accompanied by weight loss and an increase in both food intake and energy expenditure. Remarkably, neither food intake nor energy expenditure of Fgf21-deficient mice are altered by the administration of LPDs [7]. Moreover, ketogenic diets (KDs), which are widely known to induce FGF21 expression, are usually low in carbohydrates and proteins but rich in fat.…”

Section: Amino Acid-deficient and Low-protein Diets Increase Energy Ementioning

confidence: 99%

“…Macronutrients [carbohydrates, fatty acids (FAs), proteins], micronutrients (minerals and vitamins), and some bioactive dietary compounds have the capacity to regulate gene expression and thus metabolic homeostasis. In this context, it has been described that endogenous FGF21 levels are regulated by various nutritional challenges such as highfat diets (HFDs), low-protein diets (LPDs), amino aciddeficient diets, fasting, and polyphenols [6,7] (Figure 1). However, the levels of this molecule are also determined by metabolic stress, including obesity, type 2 diabetes (T2DM), and non-alcoholic fatty liver disease (NAFLD) [8].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

Pérez-Martí

Sandoval

Marrero

et al. 2016

Hormone Molecular Biology and Clinical Investigation

View full text Add to dashboard Cite

Abstract:Obesity is a worldwide health problem mainly due to its associated comorbidities. Fibroblast growth factor 21 (FGF21) is a peptide hormone involved in metabolic homeostasis in healthy individuals and considered a promising therapeutic candidate for the treatment of obesity. FGF21 is predominantly produced by the liver but also by other tissues, such as white adipose tissue (WAT), brown adipose tissue (BAT), skeletal muscle, and pancreas in response to different stimuli such as cold and different nutritional challenges that include fasting, high-fat diets (HFDs), ketogenic diets, some amino acid-deficient diets, low protein diets, high carbohydrate diets or specific dietary bioactive compounds. Its target tissues are essentially WAT, BAT, skeletal muscle, heart and brain. The effects of FGF21 in extra hepatic tissues occur through the fibroblast growth factor receptor (FGFR)-1c together with the co-receptor β-klotho (KLB). Mechanistically, FGF21 interacts directly with the extracellular domain of the membrane bound cofactor KLB in the FGF21-KLB-FGFR complex to activate FGFR substrate 2α and ERK1/2 phosphorylation. Mice lacking KLB are resistant to both acute and chronic effects of FGF21. Moreover, the acute insulin sensitizing effects of FGF21 are also absent in mice with specific deletion of adipose KLB or FGFR1. Most of the data show that pharmacological administration of FGF21 has metabolic beneficial effects. The objective of this review is to compile existing information about the mechanisms that could allow the control of endogenous FGF21 levels in order to obtain the beneficial metabolic effects of FGF21 by inducing its production instead of doing it by pharmacological administration.

show abstract

“…FGF21 is primarily stimulated in adaptation to fasting, 29 particularly protein-restriction. 30 However, prolonged systemic infusion of FGF21 in the Siberian hamster, a model with seasonal body weight fluctuation, suppresses food intake and body weight and increases energy expenditure selectively during the high body weight phase (long days), but not during the low body weight phase (short days). 31 Furthermore, a single injection of antibodies to the FGF receptor-1c splice variant with dual agonist/antagonist activity produced a long-lasting suppression of food intake and body weight in diet-induced obese mice.…”

Section: Potential Underlying Mechanisms For Change In Set Pointmentioning

confidence: 99%

Does gastric bypass surgery change body weight set point?

et al. 2016

View full text Add to dashboard Cite

The relatively stable body weight during adulthood is attributed to a homeostatic regulatory mechanism residing in the brain which uses feedback from the body to control energy intake and expenditure. This mechanism guarantees that if perturbed up or down by design, body weight will return to pre-perturbation levels, defined as the defended level or set point. The fact that weight re-gain is common after dieting suggests that obese subjects defend a higher level of body weight. Thus, the set point for body weight is flexible and likely determined by the complex interaction of genetic, epigenetic and environmental factors. Unlike dieting, bariatric surgery does a much better job in producing sustained suppression of food intake and body weight, and an intensive search for the underlying mechanisms has started. Although one explanation for this lasting effect of particularly Roux-en-Y gastric bypass surgery (RYGB) is simple physical restriction due to the invasive surgery, a more exciting explanation is that the surgery physiologically reprograms the body weight defense mechanism. In this non-systematic review, we present behavioral evidence from our own and other studies that defended body weight is lowered after RYGB and sleeve gastrectomy. After these surgeries, rodents return to their preferred lower body weight if over-or underfed for a period of time, and the ability to drastically increase food intake during the anabolic phase strongly argues against the physical restriction hypothesis. However, the underlying mechanisms remain obscure. Although the mechanism involves central leptin and melanocortin signaling pathways, other peripheral signals such as gut hormones and their neural effector pathways likely contribute. Future research using both targeted and non-targeted 'omics' techniques in both humans and rodents as well as modern, genetically targeted, neuronal manipulation techniques in rodents will be necessary.

show abstract

FGF21 is an endocrine signal of protein restriction

Cited by 464 publications

References 59 publications

A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity

A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity

Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

Does gastric bypass surgery change body weight set point?

Contact Info

Product

Resources

About