Cytokine GDF15 regulates a new energy metabolism pathway

Arya Sukumar, College of Agriculture, Vellayani

A novel pathway related to the activation of receptors associated with cardiovascular disorders like diabetes, obesity, and hypertension is described in research published in the journal Cell Reports. Many of the antidiabetic effects of PPAR β/δ receptor activators are controlled by cytokine GDF15. The research aids in the discovery of novel therapeutic routes for the treatment of metabolic disorders. Manuel Vázquez-Carrera, Faculty of Pharmacy and Food Sciences, researchers from the Institute of Biomedicine of the University of Barcelona (IBUB), and a few allied institutions led the study.

A brief overview of GDF15 and PPAR β/δ

Perosyxomel proliferator-activated receptors (PPARs) are transcription factors that belong to the hormone nuclear receptor superfamily. The malfunctioning of these receptors is linked to several metabolic and cardiovascular diseases that affect a large proportion of the population. Cytokine GDF15 is a protein produced during physiological stress. PPAR β/δ receptor activators are potential therapeutic targets for the treatment of type 2 diabetes. Functioning of PPAR β/δ anti-diabetic activator is mediated by the cytokine GDF15 (Growth/Differentiation Factor-15), and this is independent of the activation of the GDNF Family Receptor Alpha Like (GFRAL) neuronal receptor. Activation of the GFRAL receptor was previously thought to be the most well-known pathway.

Findings of the study:

This novel regulatory pathway is activated by the AMP-activated protein kinase (AMPK) protein, which is a sensor of the cell’s energy metabolism. GDF15 is a stress-response cytokine that has been suggested as a possible biomarker for a variety of diseases (heart failure, cancer, fatty liver, and so on). This cytokine is found in a wide range of cells, tissues, and organs (liver, skeletal muscle, adipose tissue, kidney, heart, placenta, macrophages, etc.). Its expression is elevated in response to intracellular organelle stress (mitochondrial or endoplasmic reticulum stress) as well as environmental influences (excess of nutrients).

 GDF15 has been demonstrated in recent research to have positive effects on metabolism via activating the GFRAL receptor in the brain. When the GFRAL receptor is activated, food intake is reduced, resulting in the reduction of weight that can help to reduce obesity and improve illnesses like type 2 diabetes. The research demonstrates how activating AMPK via GDF15 raises GDF15 levels in skeletal muscle and inexplicably, the GFRAL receptor in the brain. This pathway is thought to function as a positive feedback mechanism that keeps AMPK active for a long time. As a result, cytokine GDF15 has both central and peripheral effects. Generally, AMPK is triggered in conditions when there is a lack of cell energy and glucose. When activated, AMPK initiates a series of catabolic (degradation) activities that produce ATP while simultaneously inhibiting anabolic (synthesis) processes that utilize ATP.

Significance of the study:

Since AMPK is a major regulator of numerous processes linked to cellular energy metabolism, this activation mechanism is critical. There are presently numerous medications that activate AMPK that are deemed safe pharmaceuticals, the activation pathway of AMPK through GDF15 is a major strategy against type 2 diabetes. The potential effects of GFRAL activation via GDF15 are currently unclear. Overstimulation of this neural receptor might result in undesirable consequences. Large amounts of GDF15 produced in cancer and subsequent activation of GFRAL are responsible for the development of cachexia, i.e., severe hunger and muscle atrophy associated with this disease. As a result, researchers investigated the use of antibodies against GDF15 to combat the cachexic condition.

Conclusion:

Peroxisome proliferator-activated receptor β/δ (PPAR β/δ) stimulates AMP-activated protein kinase (AMPK), which is important for glucose and lipid metabolism. The researchers investigated whether the effects of PPAR β/δ activation depends on GDF15, a stress response cytokine that affects energy metabolism. Pharmacological activation of PPAR β/δ raises GDF15 levels and improves glucose intolerance, fatty acid oxidation, and AMPK activation in mice fed with High Fat Diet.

These effects are blocked Gdf15 -/- mice and mice injected with GDF15 neutralizing antibody. The PPAR β/δ mediated increase in the GDF15 level, which activates AMPK, is thought to be involved in the AMPK-p53 pathway. Gdf15-/- mice possess consistently lower AMPK activity in skeletal muscle, whereas GDF15 treatment activates AMPK in this organ. These findings suggest a mechanism in which PPAR β/δ activation elevates GDF15 levels via AMPK and p53, and subsequently maintains AMPK activity to mediate PPAR β/δ metabolic effects.

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Reference:

1. Aguilar-Recarte, D., Barroso, E., Gumà, A., Pizarro-Delgado, J., Peña, L., Ruart, M., Palomer, X., Wahli, W., & Vázquez-Carrera, M. (2021). GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK. Cell Reports, 36(6), 109501. https://doi.org/10.1016/j.celrep.2021.109501

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