Obesity: New Molecular Clues

 

Image: Researchers Marc Schneeberger, from UB, and Marc Claret, Miguel Servet researcher from IDIBAPS. (Photo: IDIBAPS)

It is well known that the leptin hormone plays a central role in regulating the brain’s feeling of hunger. When enough food has been eaten, this molecule is secreted by the adipose tissue to suppress appetite. However, many obese people are resistant to the effects of leptin, even though they have large amounts of leptin in their blood. To date, molecular mechanisms responsible for leptin resistance remained unknown.

Obesity is one of the most concerning epidemics of modern society. According to the World Health Organization, worldwide obesity has nearly doubled since 1980. Now, a new study, published in the journal Cell, describes a molecular mechanism that plays a central role in this public health problem. “The research shows that fat-rich diet alters appetite regulation mechanisms through its effects on Mitofusin-2 protein in hypothalamic proopiomelanocortin (POMC) neurons”, explains Marc Schneeberger, predoctoral researcher at the University of Barcelona (UB) and first author of the paper.

Why Are Neurons Resistant to Leptin?

Previous works reported that hypothalamic neurons are resistant to the effects of leptin, which inhibits the desire to eat food, and these neurons suffer endoplasmic reticulum stress. The endoplasmic reticulum is a cell organelle responsible for the formation and maturation of proteins encoded in the genome and their distribution inside and outside the cell. When this organelle does not work properly, proteins are not well formed and they accumulate, so some cellular functions are interrupted.

Mitochondria are cellular organelles related to energy generation. They constitute an important element in researches on pathologies, such as hepatic fibrosis or neurodegenerative diseases. Mitochondria are numerous inside cells and they are often attached to the endoplasmic reticulum through Mitofusin-2 protein. Researchers observed that in mice which consumed a high fat diet, the level of Mitofusin-2 in POMC neurons decreased. Consequently, the endoplasmic reticulum and mitochondria separated, causing stress in the endoplasmic reticulum and the emergence of resistance to the effects of leptin.

To better understand the role of Mitofusin-2 in the development of leptin resistance and obesity, researchers generated transgenic mice lacking Mitofusin-2 in POMC neurons. These animals eat more, gain weight due to an excessive accumulation of fat and have satiety systems and energy expenditure altered. The cause of these disorders is the presence of stress in the endoplasmic reticulum. This prevents the release of a neuropeptide that suppresses appetite. When stress in the endoplasmic reticulum is reversed through a drug treatment, changes are normalized and mice return to normal behaviour.

For the first time, this study describes a molecular mechanism that relates endoplasmic reticulum stress, resistance to leptin and appetite and body weight regulation. “The next step is to study its potential as a therapeutic target”, affirms Marc Claret, researcher at August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and coordinator of the study.

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