Researchers have found that two liver-derived molecules, GDF15 and FGF21, can work together to improve diet-induced obesity and fatty liver disease in mice. The study suggests that targeting these signaling pathways could lead to new therapeutic approaches for metabolic disorders like non-alcoholic fatty liver disease (NAFLD). This discovery provides valuable insights into the complex interplay between the liver, fat metabolism, and overall energy homeostasis.
Liver’s Role in Regulating Metabolism
The liver plays a crucial role in regulating metabolism, energy balance, and overall health. When the liver becomes overwhelmed with excess fat, it can lead to a condition called non-alcoholic fatty liver disease (NAFLD), which is closely linked to obesity and insulin resistance.
GDF15 and FGF21: Stress-Responsive Liver Molecules
GDF15 (growth differentiation factor 15) and FGF21 (fibroblast growth factor 21) are two liver-derived molecules that have garnered significant attention for their potential in treating metabolic disorders. These “stress-responsive cytokines” are produced by the liver in response to various stressors, such as excess fat accumulation, and they can help regulate energy balance and glucose homeostasis.
Exploring the Interaction between GDF15 and FGF21
In this study, the researchers aimed to investigate the interplay between GDF15 and FGF21 in the context of diet-induced obesity and fatty liver disease in mice. They used a gene delivery method to overexpress GDF15 or FGF21 specifically in the livers of the mice, which allowed them to study the effects of these molecules on metabolic health.
Beneficial Effects of GDF15 and FGF21 Overexpression
The researchers found that both GDF15 and FGF21 overexpression led to significant improvements in obesity, insulin resistance, and fatty liver disease in the mice. The mice exhibited reduced body weight, decreased fat mass, and improved lipid profiles, even when fed a high-fat diet.
Interestingly, the researchers discovered that GDF15 treatment was able to increase the production of FGF21 in the liver, whereas FGF21 treatment did not affect GDF15 levels. This suggests that the beneficial effects of GDF15 may be, at least in part, mediated through the induction of FGF21 in the liver.
Fig. 2
Mechanism: GDF15 Enhances ER Stress Response and FGF21 Induction
The researchers further investigated the underlying mechanisms by which GDF15 induces FGF21 expression. They found that GDF15 promoted the activation of the endoplasmic reticulum (ER) stress response, specifically by increasing the phosphorylation of eIF2α (a key regulator of the ER stress pathway) and the splicing of XBP1 (a transcription factor that induces FGF21 expression).
These findings suggest that GDF15 can enhance the ER stress response and, in turn, stimulate the production of FGF21 in the liver. This interplay between GDF15 and FGF21 may be a critical pathway for improving obesity-related metabolic disorders, including NAFLD.
Implications and Future Directions
The results of this study provide valuable insights into the complex regulation of metabolism by the liver and highlight the potential of targeting GDF15 and FGF21 signaling pathways for the treatment of metabolic diseases. Further research is needed to fully elucidate the therapeutic potential of these liver-derived molecules and to explore their possible application in human health.
Author credit: This article is based on research by Kento Takeuchi, Kanji Yamaguchi, Yusuke Takahashi, Kota Yano, Shinya Okishio, Hiroshi Ishiba, Nozomi Tochiki, Seita Kataoka, Hideki Fujii, Naoto Iwai, Yuya Seko, Atsushi Umemura, Michihisa Moriguchi, Takeshi Okanoue, Yoshito Itoh.
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