New research investigates the method by which our brain coordinates energy expenditure to caloric consumption.
For many, it is not an easy task to maintain a healthy body weight. Nevertheless, brains and bodies are wired to work together to maintain an energy balance.
This tight matching between the number of calories consumed versus those expended results from a complex interchange of neurobiological crosstalk within regions of the brain’s hypothalamus. When this “conversation” goes awry, obesity or anorexia can result.
Unfortunately, little is known about the details of this complex interchange despite the significant consequence. New research led by investigators at Beth Israel Deaconess Medical Center (BIDMC) provides new insights that help bring order to this complexity.
Researchers say their findings, as noted in the journal Cell, demonstrate how the neurotransmitter gamma-aminobutyric acid (GABA) selectively drives energy expenditure, and importantly, also help explain the neurocircuitry underlying the fat-burning properties of brown fat.
“Our group has built up a research program with the overall goal of unraveling the ‘wiring diagram’ by which the brain controls appetite and the burning of calories,” said senior author Bradford Lowell, M.D., Ph.D.
“To advance our understanding to this level, we need to know the function of specific subsets of neurons, and in addition, the upstream neurons providing input to, and the downstream neurons receiving output from, these functionally defined neurons. Until recently, such knowledge in the hypothalamus has been largely unobtainable.”
The hypopthalmus is a pearl-sized region that directs several important functions in the body and serves as the brain’s control center for energy balance.
This balance results when the brain receives feedback signals from the body that communicate the status of fuel stores. It then integrates this with input from the external world as well as a person’s emotional state to modify feeding behavior and energy expenditure.
In this new study, the researchers investigated a unique population of neurons that are located at the base of the brain in the hypothalamus.
“We genetically engineered mice such that they have a specific defect that prevents these neurons from releasing the inhibitory neurotransmitter, GABA,” said Lowell. “Mice with this defect developed marked obesity and, remarkably, their obesity was entirely due to a defect in burning off calories,” he explains, adding that food intake was entirely unaffected.
Researchers then engineered another group of mice in which these neurons could be selectively turned on at different times. From this the team went on to show that the neurons drive energy expenditure in brown fat.
Brown fat has been making headlines lately because many recent studies have revealed that, unlike energy-storing white fat, brown fat burns energy to generate heat. This process is called thermogenesis.
“Energy expenditure mediated by brown adipose tissue is critical in maintaining body weight and prevents diet-induced obesity. Its brain-based regulatory mechanism, however, is still poorly understood,” said first author Dong Kong, Ph.D.
“Our discovery of a hypothalamus-based neurocircuit that ultimately controls thermogenesis is an important advance,” added Lowell.
Furthermore, investigators found that when they turned on these neurons, energy expenditure was entirely dependent upon release of GABA. These results reveal that release of GABA selectively drives energy expenditure. “Our findings have greatly advanced our understanding in the control of energy expenditure and have provided novel insights into the pathogenesis of obesity,” said Kong.
The unique features of hypothalamus neurons are important because they could provide an opportunity to experimentally modify the brain’s control of energy expenditure. Specifically, neurons receiving GABA-mediated signals from these neurons are likely to play important roles in regulating energy expenditure, but not food intake.
“It is now important to fully delineate the upstream neurons that control these thermogenesis-regulating neurons, and also the downstream neurons that complete the ‘circuit’ to brown adipose tissue,” Lowell said.
Such work could uncover new opportunities for pharmacologic interventions that might lead to effective treatments for obesity and its related complications such as diabetes.