Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets

Le, Thao D. V.; Fathi, Payam; Watters, Amanda B; Ellis, Blair J.; Besing, Gai-Linn K; Bozadjieva-Kramer, Nadejda; Perez, Misty B; Sullivan, Andrew I.; Rose, Jesse P; Baggio, Laurie L.; Koehler, Jacqueline A.; Brown, Jennifer; Bales, Michelle B.; Nwaba, Kaitlyn G; Campbell, Jonathan E.; Drucker, Daniel J.; Potthoff, Matthew J.; Seeley, Randy J.; Ayala, Julio E.

doi:10.1016/j.molmet.2023.101718

Cited by 13 publications

(3 citation statements)

References 93 publications

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“…It is likely that SA may affect the central nervous system. Moreover, recent studies have shown that fibroblast growth factor-21 (FGF21) is necessary for the weight reduction generated by liraglutide in mice that were given high-carbohydrate diets [ 56 ]. The effect of SA on FGF21 levels shall be studied further in the future.…”

Section: Discussionmentioning

confidence: 99%

Development of Syringaldehyde as an Agonist of the GLP-1 Receptor to Alleviate Diabetic Disorders in Animal Models

Lee,

Li,

Cheng

et al. 2024

Pharmaceuticals

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The phenolic aldehyde syringaldehyde (SA) has been shown to have an antihyperglycemic effect in diabetic rats due to increased glucose utilization and insulin sensitivity. To understand the direct effect of SA on the GLP-1 receptor, STZ-induced diabetic rats were used. The levels of pro-inflammatory cytokines, liver enzymes, and renal function were measured using specific ELISA kits. The mechanisms of SA effects were investigated using CHO-K1 cells, pancreatic Min-6 cells, and cardiomyocyte H9c2 cells. The results indicated that the antihyperglycemic effect of SA in diabetic rats was abolished by blocking the GLP-1 receptor with an antagonist. SA has a direct effect on the GLP-1 receptor when using CHO-K1 cells transfected with the exogenous GLP-1 receptor gene. In addition, SA stimulated insulin production in Min-6 cells by activating GLP-1 receptors. SA caused a dose-dependent rise in GLP-1 receptor mRNA levels in cardiac H9c2 cells. These in vitro results support the notion that SA has a direct effect on the GLP-1 receptor. Otherwise, SA inhibited the increase of pro-inflammatory cytokines, including interleukins and tumor TNF-α, in type 1 diabetic rats in a dose-dependent manner. Moreover, as with liraglutide, SA reduced plasma lipid profiles, including total cholesterol and triglyceride, in mixed diet-induced type 2 diabetic rats. Intriguingly, chronic treatment with SA (as with liraglutide) reversed the functions of both the liver and the kidney in these diabetic rats. SA displayed less efficiency in reducing body weight and food consumption compared to liraglutide. In conclusion, SA effectively activates GLP-1 receptors, resulting in a reduction in diabetic-related complications in rats. Therefore, it is beneficial to develop SA as a chemical agonist for clinical applications in the future.

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Section: Discussionmentioning

confidence: 99%

Development of Syringaldehyde as an Agonist of the GLP-1 Receptor to Alleviate Diabetic Disorders in Animal Models

Lee,

Li,

Cheng

et al. 2024

Pharmaceuticals

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“…Protein ingestion preferentially favours gastrin and cholecystokinin, whereas carbohydrate ingestion preferentially favours gastric inhibitory polypeptide and glucagon-like peptide 1 (GLP-1). Interestingly, GLP-1 (and GLP-1 agonists) in turn act on feeding centres in the brain, promoting hepatic FGF21 production via mechanisms including adrenal cortex production of glucocorticoids [ 70 ]. One potential candidate as a systemic protein satiety hormone is glucagon, which has been implicated in the control of macronutrient selection [ 71 ] and contributes to a liver-islet alpha cell axis for the control of plasma amino acid levels, in which a high plasma amino acid level induces alpha cell hyperplasia and, in turn, increased glucagon production to stimulate amino acid breakdown [ 72 ].…”

Section: The Power Of Proteinmentioning

confidence: 99%

Protein appetite as an integrator in the obesity system: the protein leverage hypothesis

Raubenheimer,

Simpson

2023

Phil. Trans. R. Soc. B

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Despite the large volume and extensive range of obesity research, there is substantial disagreement on the causes and effective preventative strategies. We suggest the field will benefit from greater emphasis on integrative approaches that examine how various potential contributors interact, rather than regarding them as competing explanations. We demonstrate the application of nutritional geometry, a multi-nutrient integrative framework developed in the ecological sciences, to obesity research. Such studies have shown that humans, like many other species, regulate protein intake more strongly than other dietary components, and consequently if dietary protein is diluted there is a compensatory increase in food intake—a process called protein leverage. The protein leverage hypothesis (PLH) proposes that the dilution of protein in modern food supplies by fat and carbohydrate-rich highly processed foods has resulted in increased energy intake through protein leverage. We present evidence for the PLH from a variety of sources (mechanistic, experimental and observational), and show that this mechanism is compatible with many other findings and theories in obesity research. This article is part of a discussion meeting issue ‘Causes of obesity: theories, conjectures and evidence (Part II)’.

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“…Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are stress-responsive metabokines, defined as cytokines involved in the paracrine and endocrine regulation of systemic metabolism, deemed to modulate energy balance. 8 , 9 Pre-clinical data indicate that FGF21 is involved in GLP-1RA-induced weight loss 10 and is required to maximize the metabolic benefits of GLP-1RA. 11 , 12 Conversely, while GDF15 is unlikely to affect GLP-1RA action, 13 , 14 it may contribute to the magnitude of weight loss and fat mass reduction following bariatric surgery and exercise training, respectively.…”

Section: Introductionmentioning

confidence: 99%

Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids

Fiorenza,

Checa,

Sandsdal

et al. 2024

Cell Reports Medicine

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Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets

Cited by 13 publications

References 93 publications

Development of Syringaldehyde as an Agonist of the GLP-1 Receptor to Alleviate Diabetic Disorders in Animal Models

Development of Syringaldehyde as an Agonist of the GLP-1 Receptor to Alleviate Diabetic Disorders in Animal Models

Protein appetite as an integrator in the obesity system: the protein leverage hypothesis

Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids

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