Most people know a high-fat diet can affect body shape. But can it also alter brain function? A recent Yale-led study says yes.

The study, published on Sept. 5 in the journal Cell Metabolism, found diets high in fat not only caused obesity in mice, but also led to inflammation in the hypothalamus — a brain region involved in regulating hormones and metabolism. The high-fat diet, researchers found, appears to have affected the mitochondria of microglia, brain cells involved in immune response.

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“Our most important finding — that the mitochondria are very important for susceptibility to obesity — has important implications for future treatments,” said School of Medicine research scientist and the study’s first author Jung Dae Kim.

During the study, simultaneous changes in the shape of microglia suggested that the activation of these cells — the first-line defense in the inflammatory immune response in the brain — was responsible for the inflammation seen in the hypothalamus during the study.

Microglial cells can alter the normal function of neurons in the brain, and these cells have also been shown to control metabolism, Kim said.

The Yale team hypothesized that the mitochondria found in microglia might be responsible for causing these changes, he added.

Confirming this hypothesis, changes in the mitochondria of microglial cells were observed after mice that consumed a high-fat diet for three days. In these mice, a mitochondrial protein involved in regulating energy utilization called UCP2 was rapidly increased, stimulating microglia to signal to hypothalamus cells to increase appetite.

As a result, the mice became obese.

“We were intrigued by the fact that these are very fast changes that occur even before the body weight changes, and we wanted to understand the underlying cellular mechanism,” senior author and neuroscience professor Sabrina Diano told YaleNews.

And when mice lacked the UCP2 protein, microglia did not respond and the hypothalamus did not become inflamed, stopping the signals that promote obesity, according to Kim. The finding suggests that the UCP2 protein could be a target for treating metabolic disorders.

“We wanted to see the effect of deleting this protein — UCP2 — on the mitochondria and microglial cells,” Kim said. “When we deleted it, we found that no more changes happened in mitochondria, and microglia activation did not happen. The hypothalamus was not activated, either.”

The mitochondria has been suggested as a potential target for obesity interventions by other research groups. Uncovering the role of UCP2 in mice suggests the possibility of modifying this therapeutic modality.

According to the Centers for Disease Control and Prevention, an estimated 40 percent of adults in the U.S. in 2016 were obese.

Viola Lee | kyounga.lee@yale.edu