Scientists have learnt how to beat the main cause of obesity

90% of them have so-called resistance to leptin, a hormone secreted by fat cells and designed to "switch off" appetite. Normally, the human body responds to elevated leptin levels by signalling satiety. But in obese people this process is "broken": the brain does not "hear" the signal "it's time to stop".

This mystery has eluded scientists for decades, since 1994, when the laboratory of Jeffrey M. Friedman (Jeffrey M. Friedman) at Rockefeller University first isolated the gene leptin. But now a team of researchers led by Bowen Tan and Kristina Hedbacker says they have succeeded in identifying the neural mechanism for the development of leptin resistance, and more importantly, finding a way to reverse it in model mice.

Read more: A Cellular and Molecular Basis of Leptin Resistance, Cell Metabolism (2025). DOI: 10.1016/j.cmet.2025.01.001. www.cell.com/cell-metabolism/f ... 1550-4131(25)00001-4

Leptin and the "tricky" receptor target

• Normal situation: fat cells produce leptin, which, once it reaches a certain level, "orders" the brain to reduce appetite and increase energy expenditure.
• Obesity: the brain no longer responds adequately to high leptin concentrations (similar to how diabetes reduces insulin sensitivity).

The authors of a new paper published in Cell Metabolism showed that in mice on a high-calorie diet, the mTOR signalling pathway responsible for metabolic regulation and cell growth is hyperactivated. As a result, leptin, although present in large quantities, is not "perceived" by key hypothalamic neurons.

How was it possible to "switch" the signal on again

The researchers tested the drug rapamycin (rapamycin), which inhibits mTOR, on four groups of mice:

1. Healthy, fed a normal diet;
2. "Healthy" but switched to a high-fat diet (developed leptin resistance and obesity);
3. Mice that had no leptin of their own but were given leptin from outside the body;
4. Control groups with other modifications.

In the obese rodent subjects, taking rapamycin restored leptin sensitivity, so they lost weight by reducing fat mass while retaining muscle tissue. According to the researchers, this is a rare case of "selective" weight loss, in which the loss of mainly fat, not muscle - usually in the process of dieting or therapy is lost both.

The key role of POMC neurons

The authors conducted a series of experiments showing that the effects of rapamycin target a group of neurons expressing the POMC gene. These neurons have long been known to be key regulators of the effects of leptin. By activating them, the drug removes the blockage of satiety signalling. Professor Friedman says that this is consistent with previous findings: if POMC neurons are not working properly, leptin resistance develops.

Prospects and risks

• Future treatment: Scientists hope the discovery will pave the way for new anti-obesity drugs.
• Problems: Rapamycin has side effects associated with impaired glucose tolerance and diabetes risk, so a targeted approach is needed to "switch off" mTOR exclusively in POMC neurons.

Why it matters

Since 1994, researchers have tried to harness leptin in the fight against obesity, but patients typically "disobeyed" the hormone due to resistance. The new work shows a specific way this sensitivity can be restored: by suppressing abnormal mTOR activity in the brain. If a safe method can be found to locally reduce mTOR specifically in POMC neurons, then we may have a means of helping obese people not just lose weight, but do so while maintaining muscle mass and not having to deal with the "perpetual feeling of hunger".