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MicroRNA-34a and Impaired FGF19/21 Signaling in Obesity
T Fu1, J K Kemper1
1University of Illinois at Urbana-Champaign, Urbana, IL, United States.
Abstract:
The obesity epidemic and the urgent need for effective and safe drugs to treat obesity-related diseases have greatly increased research interest in the metabolic hormones, fibroblast growth factor-19 (FGF19, FGF15 in mice), and FGF21. FGF19 and FGF21 function as endocrine hormones that play key roles in energy metabolism and counteract obesity. Importantly, in obese humans and lab animals, circulating FGF19 and FGF21 levels are elevated, and metabolic actions of these hormones are impaired but the underlying mechanisms remained unknown. Recent microRNA (miR) studies have revealed that aberrantly elevated miR-34a in obesity directly targets β-Klotho, the obligate coreceptor for both FGF19 and FGF21, and attenuates metabolic signaling of these hormones. In this review, we will discuss recent findings in the miR and FGF19/21 fields, emphasizing the novel function of obesity-associated miR-34a in attenuation of FGF19/21 metabolic actions, and further discuss miRs, including miR-34a, as potential drug targets for obesity-related diseases.
Insights
Obesity is linked to impaired fibroblast growth factor (FGF19/21) signaling. Elevated miR-34a in obesity targets β-Klotho, blocking FGF19/21 actions and offering potential drug targets for metabolic diseases.
Area of Science:
- Endocrinology
- Metabolism
- Molecular Biology
Background:
- The global obesity epidemic necessitates novel therapeutic strategies.
- Fibroblast growth factor 19 (FGF19) and FGF21 are key metabolic hormones that counteract obesity.
- Elevated FGF19/21 levels and impaired signaling are observed in obesity, but mechanisms are unclear.
Purpose of the Study:
- To review recent findings on microRNAs (miRs) and FGF19/21 signaling in obesity.
- To highlight the role of miR-34a in attenuating FGF19/21 metabolic actions.
- To explore miRs as potential therapeutic targets for obesity-related diseases.
Main Methods:
- Literature review of studies on miRs, FGF19, FGF21, and obesity.
- Analysis of molecular mechanisms involving miR-34a, β-Klotho, and FGF signaling pathways.
- Discussion of preclinical and clinical findings.
Main Results:
- Obesity is associated with elevated circulating levels of FGF19 and FGF21.
- Aberrantly elevated miR-34a in obesity directly targets and downregulates β-Klotho.
- β-Klotho is an obligate coreceptor essential for FGF19 and FGF21 signaling.
- miR-34a attenuates the metabolic actions of FGF19 and FGF21.
Conclusions:
- Obesity-associated miR-34a impairs FGF19/21 metabolic signaling by targeting β-Klotho.
- miR-34a represents a novel mechanism underlying FGF19/21 resistance in obesity.
- Targeting miRs, such as miR-34a, may offer a promising therapeutic approach for obesity and related metabolic disorders.
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