What We Have Uncovered About the Brain Circuits That Regulate Feeding and Metabolism

Key regions in the brain, such as the hypothalamus and brainstem, play central roles in balancing food consumption and energy expenditure, as well as regulating other organs to adjusting processes such as insulin release from the pancreas and glucose production by the liver. Within the hypothalamus and brainstem, specialized neurons respond to changes in circulating nutrients such as glucose and hormones that signal hunger and satiety. One key example is glucagon-like peptide-1 (GLP-1). These neural populations, in turn, suppress appetite and may increase energy expenditure and regulate blood glucose. (See Figure.)

Work over the last two decades has resulted in therapies that harness these central nervous system neural populations and circuits to treat obesity and diabetes. GLP-1 receptor agonists (GLP1RAs) mimic the effects of GLP-1 and are now approved therapies for obesity. Clinical trials have shown that these are highly effective for weight loss as well as obesity-related health issues such as cardiovascular disease and nonalcoholic fatty liver. Newer therapies that combine GLP1RAs with peptides that mimic other hormones, such as glucose-dependent insulinotropic polypeptide (GIP), may prove even more effective at treating obesity and its metabolic complications.

Technological advances are now extending our understanding of the brain’s regulation of metabolism. Imaging studies that examine neural activity in animal models and humans are identifying brain regions outside the hypothalamus and brainstem that contribute to metabolic regulation. Other tools, such as single-cell and single-nucleus RNA sequencing, enable the discovery of new neural populations that respond to nutrients, to neural and hormonal signals from the gut, and to long-term changes in body weight.

Together, these approaches confirm the central role of the brain and its neural circuits in integrating information about feeding and energy to fine-tune metabolic processes. They also highlight the importance of understanding these neural circuits for developing new treatments for obesity and diabetes. For instance, it may be possible to identify additional hormone pathways for use in combination with GLP1RAs. This would allow use of GLP1RAs in lower doses, potentially reducing side effects, such as nausea and vomiting, that limit their use in some people.

Studies by researchers at the Icahn School of Medicine at Mount Sinai aim to examine the brain circuits that regulate feeding and metabolism in more detail. For example, work in The Friedman Brain Institute laboratories is examining the links between stress and metabolic diseases by mapping how stress-regulated brain circuits regulate feeding and metabolism via connections to peripheral organs.

In the laboratory of Sarah Stanley, MD, PhD, ongoing studies are examining how stress increases blood glucose. Their work demonstrates that psychological stress activates a pathway from the amygdala, a key stress-responsive brain region, via the hypothalamus and peripheral nerves to regulate glucose release from the liver. This circuit could contribute to the well-established link between stress and metabolic diseases, such as diabetes.

Recent studies from Ivan De Araujo, PhD, and colleagues examined the association of stress with gut disorders. Their research showed that chronic stress disrupts a circuit from the amygdala to the gut, resulting in alterations in the gut microbiome that increased susceptibility to gut infection and potentially altering sensory signals that provide feedback from the gut to the brain to regulate feeding.

Ongoing studies are examining the links between metabolic diseases and anxiety-related disorders. Recent studies from the laboratory of Abha Karki Rajbhandari, PhD, have shown that a high-fat diet worsened both metabolic dysfunction and behavioral measurements in a mouse model of post-traumatic stress disorder (PTSD), with marked effects on brain inflammation.

Translational studies are also examining the roles of neural circuits in the regulation of metabolism and feeding in humans. Laura Berner, PhD, and colleagues are using functional imaging approaches in humans to examine the neural mechanisms underlying a range of eating disorders, including anorexia nervosa, bulimia, and obesity. Their recent work has identified alterations in the neural circuits regulating reward processing in children with binge-eating disorder, one of the most common eating disorders.

Together, these studies may identify new therapies for obesity and diabetes by targeting specific brain and peripheral nerve circuits, such as those activated by stress, that contribute to metabolic disorders. In addition, the work may potentially lead to more personalized treatments for eating disorders and for metabolic diseases by addressing individual differences in how people regulate food intake and energy balance.

Understanding the brain circuits regulating feeding and metabolism also challenges misconceptions about obesity and diabetes. These conditions often involve complex disruptions in the brain’s regulatory systems rather than a simple lack of willpower. By advancing our understanding of the neural mechanisms regulating food intake, energy expenditure, and metabolism, we can reduce the stigma associated with obesity and diabetes and develop better therapies.