Metformin and weight loss mechanisms
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Metformin and Weight Loss: Mechanisms of Action
Appetite Suppression and Central Nervous System Effects
Metformin’s weight loss effects are primarily linked to its ability to reduce appetite. This is achieved through changes in the hypothalamus, where metformin improves leptin and insulin sensitivity, leading to decreased food intake and increased satiety. These central effects are considered multifactorial, involving modulation of hypothalamic appetite regulatory centers and possibly other neuroendocrine pathways 123.
Gut Hormones and Microbiome Modulation
Metformin stimulates the release of gut hormones such as glucagon-like peptide 1 (GLP-1), which enhances satiety and reduces hunger. Additionally, metformin alters the gut microbiome, promoting beneficial changes that may contribute to improved metabolism and reduced fat storage 234.
GDF15 and Lac-Phe: Novel Mediators of Weight Loss
Recent research has identified growth/differentiation factor 15 (GDF15) as a key mediator of metformin-induced weight loss. Metformin increases circulating GDF15, which acts on the brain to suppress appetite and reduce body weight. Studies in both humans and animal models show that the absence of GDF15 or its receptor eliminates metformin’s effects on weight, highlighting its central role 56.
Another newly discovered pathway involves the metabolite N-lactoyl-phenylalanine (Lac-Phe). Metformin induces Lac-Phe production, which also suppresses food intake and contributes to weight loss. Mice unable to produce Lac-Phe do not experience the weight-reducing effects of metformin, and human studies support its role as a downstream effector of metformin’s impact on body mass index .
Peripheral Metabolic Effects: Fat Storage and Oxidation
Metformin influences fat metabolism by reducing lipogenic gene expression, enhancing mitochondrial biogenesis, and decreasing fatty acid uptake in tissues. These effects are partly mediated by AMP-activated protein kinase (AMPK) activation, but also involve other signaling pathways such as TGF-β1/Smad3, FBP1, PP2A, FGF21, SIRT1, and mTOR. These changes collectively reduce energy intake and oppose unfavorable fat storage in the liver, skeletal muscle, and adipose tissue 124.
Impact on Hepatic Lipid Metabolism
While metformin improves insulin sensitivity and promotes weight loss, its effects on intrahepatic triglyceride content are less clear. Some studies show that metformin increases hepatic de novo lipogenesis without significantly changing fatty acid oxidation or intrahepatic triglyceride levels, suggesting that its weight loss benefits are not solely due to changes in liver fat content .
Clinical Evidence: Modest but Durable Weight Loss
Meta-analyses and systematic reviews confirm that metformin leads to modest but sustained weight loss in overweight and obese individuals, both with and without diabetes. The average reduction is around 2–3 kg, with greater effects observed in adults compared to children. The weight loss is primarily due to decreased food intake rather than increased energy expenditure, and the benefits may not persist after discontinuation of the drug 124910.
Conclusion
Metformin promotes weight loss through a combination of central appetite suppression, gut hormone modulation, changes in the gut microbiome, and direct effects on fat metabolism. Key mediators such as GDF15 and Lac-Phe play critical roles in these processes. While the weight loss is generally modest, it is durable and clinically meaningful, especially when combined with lifestyle interventions. Further research may uncover additional pathways and optimize the use of metformin for obesity management.
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