Obesity

An international research team has reported studies in mice that suggest obesity may dampen the activity of a specific population of neurons in a region of brain that is associated with controlling eating behavior, and so take the brakes off food intake to further fuel pathological eating and obesity. Their findings, reported in Science, “demonstrate how diet disrupts the function of an endogenous feeding suppression system to promote overeating and obesity,” according to the University of North Carolina’s Garret D. Stuber, PhD, and colleagues.

The scientists suggest that further work based on their discovery could ultimately point to new targets for eating disorders and obesity. Stuber is corresponding author of the team’s published paper, which is titled, “Obesity remodels activity and transcriptional state of a lateral hypothalamic brake on feeding.”

Obesity affects more than 500 million adults globally and is associated with a range of health issues that represents a major worldwide health concern, the authors wrote. While little is known about how obesity impacts on neurological mechanisms that might contribute to eating behaviors that promote obesity, prior research has suggested that the lateral hypothalamic area (LHA), an area of the brain that mediates physiological functions related to survival, may play a key role in eating behavior.

Stuber’s team carried out tests in a mouse model of obesity to look at changes in the activity of different subsets of neurons in the LHA. They first carried out high-throughput single-cell RNA sequencing to assess differential gene expression in LHA neurons in lean mice fed on a normal diet, and in obese mice fed a high-fat diet (HFD). The results highlighted a subset of glutamatergic neurons that express vesicular glutamate transporter type-2 [Vglut2; LHAVglut2 neurons] as exhibiting significant changes in the greatest proportion of genes, including many genes associated with neuronal activity.

“Consistently, LHAVglut2 neurons also contained the most significant gene-level genetic association with human body mass index (BMI), suggesting that similar alterations within LHAVglut2 neurons may contribute to human obesity,” the scientists wrote.

A series of studies using two-photon calcium imaging of single neurons showed that in control mice, individual LHAVglut2 neurons responded to the animals licking sucrose. This LHAVglut2 neuronal excitation then acted to dampen further feeding. The level of response depended on the animals’ motivation to feed. “After prefeeding, when motivation for food was low, LHAVglut2 responses of the same neurons were greater than those after a 24-hour fast,” the scientists commented. “The neural responses during sucrose consumption could thus be used to decode the motivational state of each mouse.” The difference in LHAVglut2 neuronal response to sucrose consumption was independent to differences in lick rate, “suggesting that satiety modified LHAVglut2 reward encoding independently of specific motor output.”

“Here, we demonstrate that LHAVglut2 neurons are sensitive to satiety state: when motivation for food is low, they are more excitable than when motivation is high.” Reasoning that an HFD might modify the dynamics of LHAVglut2 neuron activity, the team then demonstrated that LHAVglut2 neurons from HFD mice became progressively less responsive to sucrose consumption.

“Until now, obesity’s effects on the LHA have been unclear,” they stated. “We hypothesize that the excitatory LHAVglut2 signal represents the activation of a brake on feeding to suppress further food intake … Chronic HFD modification within LHAVglut2 cells ultimately hinders their neuronal activity, thereby weakening an endogenous attenuator of feeding to promote overeating and obesity.”

The authors acknowledge that it is not yet known whether the dampened LHAglut2 neuronal excitation induced by HFD feeding would revert back to its responsive state if diet was also normalized, or whether any other homeostatic challenges, such as dehydration, might also influence neuronal activity. “Further understanding of the multifunctionality within this population could identify new therapeutic targets for eating disorders and obesity,” the team concluded.

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