Nature Metabolism: Stanford/Harvard Team First Confirms that Metformin Suppresses Appetite through Mechanisms Separate from Exercise

"Nature Metabolism": Stanford/Harvard Team First Confirms that Metformin Suppresses Appetite through Mechanisms Separate from Exercise

On March 20, 2024, two independent research teams led by Jonathan Z. Long from Stanford University School of Medicine [1] and Lydia Lynch from Harvard Medical School [2] respectively, published two significant research findings back-to-back in the prestigious journal "Nature Metabolism," jointly revealing the key mechanisms behind metformin's appetite suppression.

Long's team first confirmed that under the influence of metformin, intestinal epithelial cells produce appetite-suppressing N-acylphenylalanine (Lac-Phe) and release it into the bloodstream [1]. It is noteworthy that Long's team had previously discovered as early as 2022 that intense exercise in humans produces Lac-Phe and suppresses appetite [3].

Lynch's team analyzed seven observational/interventional studies and found that the levels of Lac-Phe in the blood of diabetic patients treated with metformin significantly increased [2]. Importantly, whether diabetic patients or healthy subjects, their levels of Lac-Phe increased after acute metformin treatment or postprandial administration [2].

These two studies indicate that the mechanism by which metformin suppresses appetite actually converges with that of exercise.

As a well-established antidiabetic drug, the characteristic of metformin in suppressing appetite and leading to weight loss is well-known. However, the molecular mechanism by which metformin suppresses appetite is still controversial.

Lac-Phe is a metabolite discovered in recent years, and its levels in plasma increase after exercise. About two years ago, a research team led by Long discovered that Lac-Phe produced during intense exercise suppresses appetite [3].

The effect of Lac-Phe has attracted the attention of many research teams, among which are the teams led by Long from Stanford University and Lydia Lynch from Harvard Medical School.

Long's team initially confirmed, based on human blood samples and mouse experiments, that taking metformin increases plasma Lac-Phe levels in humans and mice.

In a study conducted in 2022, Long's team found that exercise promotes the production of lactate in muscles, increases lactate levels in peripheral circulation, promotes protein kinase CNDP2 to synthesize Lac-Phe from lactate and phenylalanine [3].

However, taking metformin does not increase lactate levels in the blood, so the source of lactate for promoting Lac-Phe synthesis by metformin is different from that of exercise. Subsequent studies found that metformin promotes lactate production by driving glycolysis in intestinal epithelial cells, thereby promoting Lac-Phe synthesis.

In the final stage of the research, Long's team found, based on different CNDP2 knockout mouse models (CNDP2-KO), that the blood Lac-Phe induced by metformin mainly comes from intestinal epithelial cells.

It is worth noting that the food intake and body weight of CNDP2-KO mice are no longer affected by metformin, but metformin can still regulate the blood sugar levels of CNDP2-KO mice. This also means that the mechanism by which metformin suppresses appetite is independent of its hypoglycemic mechanism.

Furthermore, Long's team also found that the appetite-suppressing effect of metformin-induced Lac-Phe is independent of the previously discovered GDF15-GFRAL signaling pathway [4].

The research conducted by Lydia Lynch's team from Harvard Medical School is entirely based on human data.

Based on seven observational/interventional clinical studies, they found that a single dose of metformin increases the levels of Lac-Phe in the blood. Moreover, their research clearly demonstrates that the increase in Lac-Phe is associated with metformin treatment rather than diabetic status.

More importantly, they also demonstrated that both healthy individuals and diabetic patients experience an increase in Lac-Phe with metformin treatment.

In summary, the two independent research findings from Jonathan Z. Long and Lydia Lynch teams collectively confirm that metformin suppresses appetite and controls weight by increasing the levels of Lac-Phe in the blood. These two research findings also provide us with new insights into the mechanism by which metformin suppresses appetite.

However, it should be pointed out that how Lac-Phe regulates food intake is still unknown. In the future, decoding the downstream signaling pathways of Lac-Phe may give rise to new anti-obesity drugs.

This article is sourced from: GEEKHEAL.COM

Zhang SY, Bruce K, Danaei Z, et al. Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake and body weight. Cell Metab. 2023;35(5):875-886.e5. doi:10.1016/j.cmet.2023.03.014