Neurons in the ventromedial nucleus of the hypothalamus that express the cholecystokinin b receptor (VMH^Cckbr neurons) appear to support glucose production during hypoglycemia without broadly controlling energy homeostasis, according to a recently published study in Molecular Metabolism. Until now, the role of these neurons in day-to-day glucose physiology and the mechanisms they use to mobilize glucose mobilization was unclear.

In the new study, researchers used continuous glucose monitoring in mice with VMH^Cckbr neurons that were chronically silenced using a tetanus toxin-based approach. They also performed acute optogenetic activation experiments and assessed hepatic glucose metabolism and white adipose tissue (WAT) lipolysis.

A Distinct, Glucose-Mobilizing Ventromedial Hypothalamic (VMH) Neuron Subset

The findings suggest VMH^Cckbr neurons represent a distinct subset of glucose-mobilizing VMH neurons that support physiologic glucose homeostasis, possibly via beta 3-adrenergic receptor (beta 3-AR)-mediated mobilization of gluconeogenic substrates and lipolysis.

“The presence of different glucose-mobilizing neuronal populations that engage distinct mechanisms in a context-dependent manner may provide the brain with flexibility to coordinate the appropriate glycemic response to different circumstances,” the authors wrote.

The VMH controls sympathetic outflow to multiple metabolic target organs, including the pancreatic islets, the liver, WAT, and brown adipose tissue. Consistent with prior reports, VMH^Cckbr neuron activation supported that lipolysis and signaling through the beta 3-AR was required for glycerol mobilization. It is unclear whether this occurs via direct sympathetic nervous system (SNS) innervation of WAT or through changes in circulating catecholamines, although levels of the latter have been shown to increase following VMH^Cckbr neuron activation.

The authors noted that a high-fat diet can rapidly increase insulin resistance through excessive SNS activity and WAT lipolysis. The researchers’ next plan to examine whether dysregulation of VMH^Cckbr neurons and related central nervous system circuits that contribute to SNS outflow and lipolysis occur during obesity and diabetic states.

Clinical Implications and Role in Prediabetes

“We wanted to understand whether it is also important in controlling blood sugar during day-to-day activities because that’s when diabetes develops,” said Alison Affinati, MD, PhD, assistant professor of internal medicine and member of Caswell Diabetes Institute at the University of Michigan, Ann Arbor, Michigan, in a press release. “In the first 4 hours after you go to bed, these neurons ensure that you have enough glucose so that you don’t become hypoglycemic overnight.”

These new findings may help explain what happens in patients with prediabetes, who often have increased lipolysis during the night. The researchers believe that in these patients, the VMH^Cckbr neurons could be overactive, contributing to higher blood sugar.

“Our studies show that the control of glucose is not an on-or-off switch as previously thought,” Affinati added. “Different populations of neurons work together, and everything gets turned on in an emergency. However, under routine conditions, it allows for subtle changes.”

A Potential Pharmacologic Target

Looking forward, it is hoped that VMH^Cckbr neurons may represent a pharmacologic target to improve glycemic control in multiple forms of diabetes. The VMH comprises several populations of glucose-mobilizing neurons that engage different mechanisms, such as controlling WAT lipolysis and providing substrates for gluconeogenesis to regulate glucose metabolism across multiple contexts.

The authors propose that VMH^Cckbr neurons, and the central nervous system more broadly, help maintain adequate blood glucose during the transition from feeding to fasting. During early fasting, insulin decreases while hormonal and nutrient signals shift liver physiology toward gluconeogenesis. At the same time, the brain increases lipolysis through SNS activation to provide glycerol for gluconeogenesis.

Research support was provided by the Michigan Diabetes Research Center, the Mouse Metabolic Phenotyping Center — Live Physiology Phenotyping Core, the Michigan Nutrition and Obesity Center Adipose Tissue Core, Department of Veterans Affairs, the Warren Alpert Foundation, Endocrine Fellows Foundation, Marilyn H. Vincent Foundation, and Novo Nordisk. This work was also supported in part by a National Institutes of Health grant.