Researchers uncover neural mechanism behind leptin resistance and a approach to reverse it

Worldwide weight problems charges have greater than doubled since 1990, with practically a billion folks now falling into the class. Although a posh interaction of genes, weight-reduction plan, and surroundings contribute, 90% of circumstances share one factor in widespread: leptin resistance.

In lean people, fats cells produce the hormone leptin, which suppresses urge for food. However in most people with weight problems, this sign fails to register. Why this occurs has been a thriller for greater than three a long time, ever since Jeffrey M. Friedman’s laboratory on the Rockefeller College cloned the leptin gene in 1994.

However now Bowen Tan, Kristina Hedbacker, and different researchers in Friedman’s Laboratory of Molecular Genetics have found a neural mechanism concerned in leptin resistance-and, crucially, a approach to reverse it in mice utilizing a well known drug. Because the researchers describe in a brand new paper in Cell Metabolism, the drug rapamycin restores leptin sensitivity to diet-induced overweight mice, resulting in important lack of fats with solely minimal results on muscle.

“Earlier than our analysis, the explanation for weight problems in diet-induced overweight mice was unknown, leaving a essential hole in our understanding of how leptin resistance develops and the way it may be reversed,” says Tan, co-first creator and a graduate pupil in Friedman’s lab.

“Although Jeff Friedman found this highly effective hormone again in 1994, its full potential to assist folks drop a few pounds hasn’t been realized as a result of most overweight sufferers have acquired resistance to leptin,” says co-first creator Hedbacker, a analysis specialist at HHMI and a member of Friedman’s lab. “It is actually thrilling to suppose that there could also be means for addressing this.” 

An excessive amount of of a superb factor

Lengthy earlier than plant agriculture and animal domestication supplied extra dependable entry to vitamins, people routinely confronted hunger. That is when the leptin circuit developed. Neurons within the hypothalamus-the mind’s energy-balance regulator-pick up satiety alerts from fats, which secretes leptin; a excessive quantity of the hormone alerts that there are enough fats shops and the vitality tank is full, whereas a low leptin degree signifies that the physique is operating on fumes.

Our brains retain this technique for regulating meals consumption, whilst circumstances round it have drastically modified, with extra folks gaining access to high-calorie meals than ever earlier than. Knowledge counsel that as weight is gained and leptin ranges regularly rise, the mind progressively stops responding to leptin.

This phenomenon is analogous to insulin resistance, which is the commonest explanation for diabetes and a situation that develops over time, due, partly, to chronically elevated insulin ranges. Equally, most individuals with weight problems have excessive leptin, however reception of their leptin signaling is blocked. This makes it very tough to drop a few pounds, as a result of the mind doesn’t obtain the suitable sign of how a lot fats is saved.”

Kristina Hedbacker, co-first creator

With this in thoughts, Tan and Hedbacker got down to determine biomarkers within the 10% of sufferers with weight problems who’re leptin delicate and will probably profit from leptin therapy. They appeared in each leptin-sensitive and leptin-resistant mice.

What they found despatched them down an sudden path. They discovered that in leptin-resistant mice, the degrees of two important amino acids are dysregulated in response to leptin. These two amino acids, methionine and leucine, are recognized activators of a signaling molecule referred to as mTOR (quick for “mammalian goal of rapamycin”). Leptin-sensitive animals confirmed no such dysregulation.

“With this as a place to begin, we discovered that mTOR is hyperactive in particular mind areas and cell sorts in overweight animals,” Tan says.

Weight reduction

To research additional, the researchers examined the results of rapamycin, an mTOR inhibitor, in 4 teams of mice: leptin-sensitive mice fed a low-calorie chow weight-reduction plan, mimicking individuals who stay lean; mice fed a high-fat weight-reduction plan that developed leptin resistance, much like individuals who develop weight problems; and two units of overweight mice that have been leptin poor however attentive to the hormone. These mice have been fed both the low-calorie chow weight-reduction plan or the high-fat weight-reduction plan. 

The outcomes have been putting: “Overweight mice fed a high-fat weight-reduction plan and handled with the mTOR inhibitor rapamycin misplaced important quantities of weight, which-similar to leptin therapy in leptin-sensitive animals-was primarily attributable to a lower within the quantity of adipose tissue,” Tan says.

Lack of fats mass with out muscle mass is attribute of leptin therapy, however it’s uncommon for weight reduction basically. For instance, weight reduction achieved by weight-reduction plan or therapy with extremely efficient anti-obesity medicines corresponding to Ozempic results in a major lack of each fats and muscle.

They then investigated which cell sorts within the mind have been the goal of rapamycin, specializing in a dozen cell sorts within the hypothalamus, the place leptin is understood to behave. Utilizing single-cell sequencing, Tan discovered that rapamycin therapy exerted important results on neurons within the hypothalamus that specific a gene referred to as POMC. These neurons are recognized to mediate leptin’s weight-reducing results.

“We discovered that rapamycin lowered mTOR in POMC neurons and restored their receptivity, primarily resensitizing the animals to leptin and resulting in a decreased measurement of fats depots relative to muscle mass,” Hedbacker says. 

Defects in POMC-expressing neurons are additionally recognized to trigger leptin resistance and weight problems, Friedman notes, including, “it was satisfying to search out that an acquired type of leptin resistance targets this identical pathway.”

By exhibiting that’s attainable to revive leptin signaling, the findings might probably result in new weight problems remedies. Future analysis in Friedman’s lab will discover why a high-fat weight-reduction plan elevates mTOR signaling within the mind. The lab may even attempt to develop means for inhibiting mTOR particularly in POMC neurons to keep away from potential negative effects of systemic rapamycin use, which is linked to glucose intolerance and probably diabetes.