How brain cells use fat determines weight gain in mice

The study could help scientists identify a potential target for treating obesity and Type 2 diabetes.


Astrocytes, a type of brain cell, are one of the key players in regulating brain functions. The role of astrocytes has also recently been identified in the hypothalamic control of energy balance.

Astrocytes use both glucose and fatty acids for fuel. However, how fatty acids affect astrocyte function remains elusive.

A new study by Yale scientists reveals how fatty acids affect astrocytes’ function and are mediated by diet.

Scientists studied a brain pathway that helps control satiety or the feeling of being full after eating. This study was conducted on mice models. When a mouse eats, neurons in an area of the brain called the hypothalamus start to fire, sending a signal of ‘satiation.’ This causes them to stop eating. Interaction of these neurons with Astrocytes, helping deliver that signal.

Scientists noted, “The astrocytes’ ability to support these neurons, however, depends on the fuel they can access. If astrocytes can use fatty acids, then astrocytes help neurons signal satiety. However, the ability to utilize fatty acids for this purpose is highly contingent on a diet.”

When scientists fed mice with a high-fat diet, they found that astrocytes could not use fatty acids for fuel. This limits the neurons’ ability to signal satiety and ultimately promotes weight gain.

Tamas Horvath, the Jean and David W. Wallace Professor of Comparative Medicine at Yale School of Medicine and senior author of the study said, “So, fat itself is protecting mice from gaining weight on a high-fat diet, but only as long as fat can enter astrocytes. Astrocytes’ ability to use fat determines a mouse’s susceptibility to diet-induced obesity.”

Scientists found two leading players in this process: ANGPTL4 (Angiopoietin-like 4) and PPARγ(peroxisome proliferator-activated receptor-gamma).

Scientists noted, “The molecule ANGPTL4 (Angiopoietin-like 4) reduces the availability of fatty acids. But when mice were fed a high-fat diet, this molecule became overactive, leading to a reduction in the fatty acids that were available for astrocytes to use and, eventually, weight gain. Suppressing ANGPTL4 function, the mice remained lean even when they were fed a high-fat diet. This was due to the activity of another molecule called PPARγ(peroxisome proliferator-activated receptor-gamma).”

Horvath said“PPARγ is the machinery that enables fats to be used by astrocytes. Removing ANGPTL4 leads to more PPARγ activation.”

“And with more PPARγ activation, there are more fatty acids for astrocytes to use and a reduced likelihood of gaining weight.”

“Understanding how these molecules affect astrocyte function and, ultimately, weight gain may help us target them for treatment of certain health conditions.”

“Weight gain itself is not a threat to health; complications that can arise from weight gains, such as Type 2 diabetes and cardiovascular issues, are.”

“Hypothetically, we can target this cellular machinery to promote fat uptake by astrocytes and, through that, prevent weight gain and the dangerous comorbidities that can come with it.”

This work was a collaborative study between the laboratories of Horvath and Carlos Fernandez-Hernando, the Anthony N. Brady Professor of Comparative Medicine. It was led by Luis Varela, an associate research scientist at the Yale School of Medicine and the first author of the study.

Journal Reference:

  1. Luis Varela, Jae Geun Kim et al. Astrocytic lipid metabolism determines susceptibility to diet-induced obesity. Science Advances, 2021; DOI: 10.1126/sciadv.abj2814
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