Trends in Endocrinology & Metabolism
ReviewHypothalamic Control of Systemic Glucose Homeostasis: The Pancreas Connection
Section snippets
Historical Essentials
The first evidence that the brain influences glucose metabolism was provided by Claude Bernard in 1849. He observed that stimulation of the base of the fourth ventricle in rabbits caused a dramatic rise in blood glucose. The notion that the brain was the only relevant location for glucoregulation was widely accepted until Banting and colleagues discovered insulin in 1921. These findings heralded an era devoted to investigating the mechanisms of insulin secretion and action in physiology and
Location of Glucose-Sensing Neurons
Glucose is the prime cellular energy source to sustain life, and therefore its availability must be constantly monitored. Higher organisms have developed dedicated sensor and effector mechanisms to maintain systemic glucose homeostasis 4, 5. The brain uses ∼60–70% of the total glucose. It predominantly expresses the high-affinity transporters GLUT-1 and GLUT-3, allowing effective glucose transport at normal circulating range. Thus the brain does not depend on insulin for glucose uptake, even
Hypothalamic Control of Hepatic Glucose Production (HGP)
HGP is one of the major processes implicated in systemic glucose homeostasis. Ample evidence indicates that the hypothalamic action of metabolic hormones (insulin and leptin) and nutrients influences HGP in rodents [14]. Hypothalamic leptin, preferentially via POMC neurons, suppresses HGP and increases insulin-independent tissue glucose uptake [14]. The beneficial effects of hypothalamic leptin action on HGP are also apparent in pathophysiological conditions such as diet-induced insulin
Hypothalamic Control of Glucose Metabolism in Skeletal Muscle
Skeletal muscle is the major site for glucose disposal, but current understanding of underlying hypothalamic mechanisms is scarce. Intracerebroventricular (i.c.v.) insulin augments muscle glycogen synthesis and this is prevented by glucose coinfusion [20]. Leptin microinjection into the VMN, but not into other hypothalamic nuclei, preferentially increases glucose uptake in skeletal muscle and heart 21, 22. These effects are mediated via the melanocortin system: VMN leptin action is abolished by
Hypothalamic Control of Glucose Metabolism in Adipose Tissue
Glucose uptake in WAT is largely dependent on insulin action, although it only accounts for about 5–10% of total. However, WAT supplies gluconeogenic precursors (glycerol and non-esterified free fatty acids) for HGP, thus efficient control of lipolysis contributes to coordinating glycemia and adiposity.
The evidence suggests that lipid mobilization is divergently regulated by hypothalamic insulin and leptin. Infusion of insulin into the mediobasal hypothalamus of rodents suppresses sympathetic
Hypothalamic Control of Pancreatic Function
The principal role of the endocrine pancreas, represented by the islets of Langerhans, is to maintain systemic glucose homeostasis. It has been known for decades that the brain influences pancreatic islet physiology via sympathetic and parasympathetic inputs, thus fine-tuning endocrine functions according to metabolic needs. However, our understanding of the neurocircuits and molecular mechanisms involved is still rudimentary. This section summarizes current knowledge of hypothalamic control of
Evidence for Central Control of Glucose Homeostasis in Humans
Substantial evidence in rodents supports the notion that the hypothalamus plays a role in systemic glucose homeostasis. However, given the artificial nature of the experimental strategies used (suprapharmacology, genetic modifications, opto- and chemogenetics), the real contribution of brain mechanisms to physiological glucose control is controversial. This discussion is especially relevant in the context of human biology, but in this regard obvious methodological difficulties arise.
Indirect
Concluding Remarks
The brain controls many essential homeostatic functions, and therefore it seems implausible that glucose metabolism is entirely regulated by a peripheral mechanism. In recent years major advances in mouse genetics and experimental technology have substantially consolidated the pioneering concept that suggests a role for the brain in peripheral control of glucose metabolism. Extensive literature posits the hypothalamus as an important glucoregulatory center, and there is little doubt that it can
Acknowledgments
We would like to thank Servier Medical Art and Paxinos and Franklin’s The Mouse Brain in Stereotaxic Coordinates for figure graphics. This work was supported by the European Research Council (ERC) under the EU Horizon 2020 Research and Innovation Program (grant agreement 725004) and CERCA Programme/Generalitat de Catalunya. M.C. is a recipient of a Miguel Servet 2 contract (MSII15/00025) from the Instituto de Salud Carlos III, cofinanced by the European Regional Development Fund (ERDF) – ‘A Way
Glossary
- Chemogenetics
- a technology used in neuroscience to remotely modulate the activity of specific neuronal subsets in freely moving animals. It is based on the use of ‘designer receptors exclusively activated by designer drugs’ (DREADDS) that are activated by otherwise inert compounds. It is an alternative to optogenetics, and allows long-timescale interventions.
- Depolarization
- a rapid shift of the cell-membrane resting potential, becoming temporarily less negative. This is achieved via opening of
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2022, Journal of Functional FoodsCitation Excerpt :The mechanisms by which calorie intake is also reduced in M150 SIT animals cannot be explained by the changes in gene expression at the hypothalamic level. On the other hand, the hypothalamic connection with the pancreas reveals as the hypothalamus controls the systemic insulin homeostasis (Pozo & Claret, 2018). In this sense, ventricular delivery of NPY promotes pancreas insulin secretion (Marks & Waite, 1996), which could tentatively link the increased Lepr gene expression and the decreased (a trend) Npy mRNA levels, with the reduced insulin circulating levels observed in MET (150 mg/kg of body weight) treated animals.