Hypothalamus neurons help maintain blood sugar levels at night

We are used to thinking that the brain interferes with blood sugar regulation only in “extreme situations” – during hypoglycemia or prolonged starvation. A new study in Molecular Metabolism shows that specialized neurons in the ventromedial nucleus of the hypothalamus (VMH) that express the cholecystokinin receptor CCK-B – VMH^Cckbr – help keep glucose levels normal every day during short natural fasts, such as at night between dinner and breakfast. They do this not through the pancreas, but by triggering the mobilization of “fuel” for gluconeogenesis: they enhance lipolysis in adipose tissue, increasing the level of glycerol – a key substrate for hepatic glucose synthesis. This is how the brain subtly insures us against sugar dips in everyday life, without “sirens and flashing lights.”

Background of the study

Maintaining normal blood sugar between meals is not just the "pancreas's business." During short natural fasts (for example, at night), the liver switches to endogenous glucose production: first it uses up glycogen, then activates gluconeogenesis. One of the key "building blocks" for the synthesis of new glucose is glycerol, which comes from adipose tissue during lipolysis. That is why the quality of the "night fuel" and its timely supply are so important for even glycemia before breakfast.

In addition to hormones, the brain is also responsible for this fine coordination - primarily the ventromedial nucleus of the hypothalamus (VMH), long known as a node that, via the sympathetic nervous system, can "twist" fat metabolism and, consequently, the availability of substrates for the liver. Classical studies on rodents showed that stimulation of the VMH causes lipolysis in white adipose tissue, and blockade of β-adrenergic receptors dampens this response; more recent studies have supplemented the picture with the participation of glial and other hypothalamic circuits that increase the content of norepinephrine in adipose tissue and thereby trigger the breakdown of triglycerides.

Within the VMH itself, neurons are heterogeneous - different populations control different "shoulders" of energy. CCK-sensitive circuits have attracted particular interest in recent years: it has been shown that cholecystokinin from the parabrachial nuclei "awakens" the VMH for counter-regulatory responses to hypoglycemia, and the VMH itself contains a large proportion of cells with the CCK-B receptor. Against this background, a hypothesis has emerged that CCK-B neurons of the VMH participate not only in emergency reactions, but also in everyday glucose retention during short fasts - through the control of lipolysis and the supply of glycerol to the liver. It is precisely this role for VMH^Cckbr neurons that the current work in Molecular Metabolism is testing.

The clinical context is clear: people with diabetes and prediabetes often exhibit the “dawn phenomenon” – a morning rise in blood sugar due to increased nocturnal endogenous glucose production in the presence of relative insulin deficiency. This nocturnal balance is influenced by both circadian mechanisms (the SCN clock alters the rhythm of hepatic glucose sensitivity and endogenous glucose production) and central sympathetic circuits. Understanding how specific VMH neuronal populations dose nocturnal lipolysis and thereby “draw” glycerol for the liver helps to connect the basic neurobiology with the practical phenotype of morning hyperglycemia – and suggests new research applications.

How it was tested: from neural selectivity to systemic effect

The team worked on mice and used genetic tools to specifically turn VMH^Cckbr neurons on/off, then tracked the dynamics of glucose, lipolysis, and metabolites in the blood in detail. The key experiments were tailored to a short overnight fast, as close as possible to normal physiology. When these neurons were turned off, the mice were worse at maintaining glycemia during the fast; when they were activated, glycerol increased in the blood - it is what "feeds" liver gluconeogenesis and protects the brain and heart from sugar deficiency. In parallel, the authors excluded "bypass" pathways through islet hormones and tracked the contribution of the sympathetic nervous system.

What exactly did they find?

• These neurons store sugar at night. VMH^Cckbr cells maintain glucose during short fasts by triggering lipolysis and supplying glycerol to the liver.
• The mechanism is through fat, not through insulin/glucagon. The shift occurs primarily along the "adipose tissue → liver" axis, and not through a direct effect on islet hormones.
• Circuit hyperactivity may explain prediabetic “nights.” Increased nocturnal lipolysis has been described in people with prediabetes; the authors suggest that overdrive of VMH^Cckbr neurons may drive morning sugar spikes. This could be a clue for future targeted interventions.
• Regulation is distributed. VMH^Cckbr neurons are "in charge" of lipolysis; other populations in the VMH probably control other arms of the glucose balance - the brain distributes roles between different cell types.

Why does this change the picture?

Classic textbooks depict the brain as a glucose “emergency dispatcher.” These data shift the focus: the central nervous system constantly “steers” metabolism to smooth out sugar fluctuations between meals. For the clinic, this means that in the case of early carbohydrate metabolism disorders, it is worth looking not only at the liver, muscles, and pancreas, but also at the central circuits that set the background rate of lipolysis and the supply of substrates for gluconeogenesis.

A bit of context

It has been previously shown that subsets of VMH neurons can alter blood sugar independently of classical hormonal responses, likely via sympathetic outputs to the liver and white adipose tissue. The new work neatly nails this scenario to everyday physiology and singles out a specific population, Cckbr neurons, as gatekeepers of nocturnal glycemia.

What this could mean for patients

• Understanding morning sugar more broadly. If a person has normal dinners, but in the morning glycemia is consistently high, part of the puzzle may lie in the central regulation of lipolysis at night. This does not cancel the role of insulin resistance, but adds another "handle".
• New application points: In the long term, strategies that gently dampen excessive nocturnal lipolysis signaling (e.g. via sympathoadrenal transmission or local receptors) may be possible as an adjuvant to standard prediabetes/T2DM therapy.
• Precise stratification. It makes sense to differentiate phenotypes: some have a liver "leading defect", some have a muscular defect, and some have a neuron-mediated nocturnal defect. This is important for selecting behavioral and pharmacological interventions.

Methodological strengths and limitations

The work combines neural selectivity (manipulation of VMH^Cckbr neurons) with systemic metabolic measurements in a realistic short-fasting regime. But:

• This is a mouse study - caution is required when translating to humans;
• The authors identify one “lever” (lipolysis); other arms of glucose regulation are probably controlled by other neuronal populations;
• clinical conclusions - hypotheses that need to be tested in pilot studies in humans (for example, monitoring night-time lipolysis dynamics and sugar with indirect markers of sympathetic activity).

Where is it logical to move next?

• Map the entire circuit: inputs to VMH^Cckbr and outputs to adipocytes/liver; check the contribution of the sympathoadrenal arch.
• Test "human" markers: is there a relationship between variation in the activity of this circuit and nocturnal lipolysis/morning glycemia in humans (e.g. by combining continuous glucose monitoring and lipolysis biomarkers).
• Test interventions: central receptor/descending pathway pharmacology; behavioral manipulations (dinner timing, macronutrient composition) that reduce nocturnal gluconeogenesis demand.

Briefly - three facts

• VMH^Cckbr neurons in the brain maintain glucose during short fasting, including overnight fasting, by enhancing lipolysis and glycerol supply to the liver.
• This mechanism is daily, not emergency: the brain constantly “steers” glucose homeostasis between meals.
• Overactivity of the circuit may fuel prediabetic morning sugar surges - a potential target for future interventions.

Study source: Su J. et al. Control of physiologic glucose homeostasis via hypothalamic modulation of gluconeogenic substrate availability. Molecular Metabolism (online July 18, 2025; No. 99:102216; DOI 10.1016/j.molmet.2025.102216 ).