Hypothalamic Control of Systemic Glucose Homeostasis: The Pancreas Connection

doi:10.1016/j.tem.2018.05.001

Trends in Endocrinology & Metabolism

Volume 29, Issue 8, August 2018, Pages 581-594

https://doi.org/10.1016/j.tem.2018.05.001 Get rights and content

Highlights

Fluctuations in hormones and glucose levels are sensed by specific subsets of hypothalamic neurons as a proxy for overall metabolic status.

The hypothalamus integrates this information and accordingly modulates effector mechanisms to maintain metabolic homeostasis.

Glucose homeostasis is achieved by coordinating hepatic glucose production, muscle and fat glucose uptake, as well as endocrine pancreas function.

The ventromedial hypothalamus is a crucial nexus in the initiation of the glucose counter-regulatory response which is partially mediated via glucagon release by the pancreas.

The arcuate nucleus of the hypothalamus is preferentially implicated in fine-tuning insulin release.

Maintenance of glucose homeostasis is mandatory for organismal survival. It is accomplished by complex and coordinated interplay between glucose detection mechanisms and multiple effector systems. The brain, in particular homeostatic regions such as the hypothalamus, plays a crucial role in orchestrating such a highly integral response. We review here current understanding of how the hypothalamus senses glucose availability and participates in systemic glucose homeostasis. We provide an update of the relevant signaling pathways and neuronal subsets involved, as well as of the mechanisms modulating metabolic processes in peripheral tissues such as liver, skeletal muscle, fat, and especially the pancreas. We also discuss the relevance of these networks in human biology and prevalent metabolic conditions such as diabetes and obesity.

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

References (97)

S. Stanley
Profiling of glucose-sensing neurons reveals that GHRH neurons are activated by hypoglycemia
Cell Metab.
(2013)
T. Shiuchi
Hypothalamic orexin stimulates feeding-associated glucose utilization in skeletal muscle via sympathetic nervous system
Cell Metab.
(2009)
T. Scherer
Brain insulin controls adipose tissue lipolysis and lipogenesis
Cell Metab.
(2011)
S.M. Steculorum
AgRP neurons control systemic insulin sensitivity via myostatin expression in brown adipose tissue
Cell
(2016)
K.K. Ishihara
Brain insulin infusion does not augment the counterregulatory response to hypoglycemia or glucoprivation
Metabolism
(2009)
M.C. Vogt
Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding
Cell
(2014)
Q. Tong
Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia
Cell Metab.
(2007)
H. Dhillon
Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis
Neuron
(2006)
P.A. Smeets
Functional MRI of human hypothalamic responses following glucose ingestion
Neuroimage
(2005)
J.K. Young
The brain response to 2-deoxy glucose is blocked by a glial drug
Pharmacol. Biochem. Behav.
(2000)

C. Garcia-Caceres

Astrocytic insulin signaling couples brain glucose uptake with nutrient availability

Cell

(2016)

L. Steinbusch

Brain glucose sensing in homeostatic and hedonic regulation

Trends Endocrinol. Metab.

(2015)

A.S. Garfield

A parabrachial–hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia

Cell Metab.

(2014)

R. Coppari

The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity

Cell Metab.

(2005)

T. Fujikawa

Leptin engages a hypothalamic neurocircuitry to permit survival in the absence of insulin

Cell Metab.

(2013)

J. Mayer

The glucostatic theory of regulation of food intake and the problem of obesity

Bull. New Engl. Med. Cent.

(1952)

Y. Oomura

Reciprocal activities of the ventromedial and lateral hypothalamic areas of cats

Science

(1964)

B.K. Anand

Activity of single neurons in the hypothalamic feeding centers: effect of glucose

Am. J. Physiol.

(1964)

K. Timper et al.

Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity

Dis. Model. Mech.

(2017)

V.H. Routh

Hypothalamic glucose sensing: making ends meet

Front. Syst. Neurosci.

(2014)

X. Fioramonti

Recent advances in the cellular and molecular mechanisms of hypothalamic neuronal glucose detection

Front. Physiol.

(2017)

D. Wang

Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons

Front. Neuroanal.

(2015)

T. Shimazu et al.

Systemic glucoregulation by glucose-sensing neurons in the ventromedial hypothalamic nucleus (VMH)

J. Endocr. Soc.

(2017)

T. Shimazu

Reciprocal influences of the ventromedial and lateral hypothalamic nuclei on blood glucose level and liver glycogen content

Nature

(1966)

M.L. Ashford

Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K⁺ channels

Pflugers Arch.

(1990)

A.A. Dunn-Meynell

Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons

Diabetes

(2002)

M. Claret

AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

J. Clin. Invest.

(2007)

J. Ruud

Neuronal control of peripheral insulin sensitivity and glucose metabolism

Nat. Commun.

(2017)

A. Pocai

Central leptin acutely reverses diet-induced hepatic insulin resistance

Diabetes

(2005)

P.M. Titchenell

Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo

Nat. Commun.

(2015)

C.J. Ramnanan

Interaction between the central and peripheral effects of insulin in controlling hepatic glucose metabolism in the conscious dog

Diabetes

(2013)

B.E. Levin et al.

Peripheral glucose homeostasis: does brain insulin matter?

J. Clin. Invest.

(2011)

J.M. Rojas et al.

Control of hepatic glucose metabolism by islet and brain

Diabetes Obes. Metab.

(2014)

C. Perrin

Intracerebroventricular infusion of glucose, insulin, and the adenosine monophosphate-activated kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, controls muscle glycogen synthesis

Endocrinology

(2004)

Y. Minokoshi

Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats

Diabetes

(1999)

M.S. Haque

Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats

Diabetes

(1999)

C. Toda

Distinct effects of leptin and a melanocortin receptor agonist injected into medial hypothalamic nuclei on glucose uptake in peripheral tissues

Diabetes

(2009)

E.A. Coutinho

Activation of SF1 neurons in the ventromedial hypothalamus by DREADD technology increases insulin sensitivity in peripheral tissues

Diabetes

(2017)

C. Buettner

Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms

Nat. Med.

(2008)

M.N. Brito

Differential activation of the sympathetic innervation of adipose tissues by melanocortin receptor stimulation

Endocrinology

(2007)

R. Nogueiras

The central melanocortin system directly controls peripheral lipid metabolism

J. Clin. Invest.

(2007)

D.A. Morgan

Regulation of glucose tolerance and sympathetic activity by MC4R signaling in the lateral hypothalamus

Diabetes

(2015)

W. Rosario

The brain-to-pancreatic islet neuronal map reveals differential glucose regulation from distinct hypothalamic regions

Diabetes

(2016)

M.A. Osundiji

Brain glucose sensors play a significant role in the regulation of pancreatic glucose-stimulated insulin secretion

Diabetes

(2012)

T.K. Lam

Regulation of blood glucose by hypothalamic pyruvate metabolism

Science

(2005)

M. Chen

Effect of cerebral intraventricular insulin on pancreatic insulin secretion in the dog

Diabetes

(1975)

T.T. Yang

Opening of ATP-sensitive potassium channel by insulin in the brain-induced insulin secretion in Wistar rats

Horm. Metab. Res.

(2010)

S. Obici

Hypothalamic insulin signaling is required for inhibition of glucose production

Nat. Med.

(2002)

Cited by (52)

Hypothalamic NPFFR2 attenuates central insulin signaling and its knockout diminishes metabolic dysfunction in mouse models of diabetes mellitus
2024, Clinical Nutrition
The hypothalamus is a crucial brain region that mediates the effects of insulin and leptin signals on peripheral metabolic functions. Previous research has shown that insulin signals in the hypothalamus act via multiple neuronal circuits and anabolic/catabolic pathways that converge on the vagus nerve and sympathetic fibers to coordinate energy metabolism in peripheral organs. Additionally, neuropeptide FF (NPFF) has been identified as a regulator of feeding behaviors and energy homeostasis in the hypothalamus, but the mechanisms underlying its involvement in metabolic control remain unclear. This study aims to explore the underlying mechanisms of NPFF in modulating metabolic disorders.
In this study, we investigated the physiological role of NPFF in insulin-related energy homeostasis and metabolic health. First, we evaluated the effects of NPFF and its receptors on central insulin signaling using mouse hypothalamic cell lines and Npffr2-overexpressing mice. To further explore the effects of NPFFR2 on insulin-related metabolic disorders, such as diabetes mellitus, we used Npffr2-deleted mice in combination with the streptozotocin (STZ)-induced type 1 diabetes and high-fat diet/STZ-induced type 2 diabetic mouse models. The impacts of central NPFFR2 were demonstrated specifically through Npffr2 overexpression in the hypothalamic arcuate nucleus, which subsequently induced type 2 diabetes.
We found that stimulating NPFFR2 in the hypothalamus blocked hypothalamic insulin activity. Npffr2 deletion improved central and peripheral metabolic symptoms in both mouse models of diabetes mellitus, exerting effects on central and systemic insulin resistance, feeding behaviors, glucose and insulin intolerance, lipid metabolism, liver steatosis, and inflammation of white adipose tissues. The overexpression of ARC Npffr2 augmented the metabolic dysregulation in the mouse model of type 2 diabetes.
Our findings demonstrate that hypothalamic NPFFR2 negatively regulates insulin signaling in the central nervous system and plays an important role in maintaining systemic metabolic health, thereby providing valuable insights for potential clinical interventions targeting these health challenges.
Maternal Western diet programs cardiometabolic dysfunction and hypothalamic inflammation via epigenetic mechanisms predominantly in the male offspring
2024, Molecular Metabolism
Maternal exposure during pregnancy is a strong determinant of offspring health outcomes. Such exposure induces changes in the offspring epigenome resulting in gene expression and functional changes. In this study, we investigated the effect of maternal Western hypercaloric diet (HCD) programming during the perinatal period on neuronal plasticity and cardiometabolic health in adult offspring.
C57BL/6J dams were fed HCD for 1 month prior to mating with regular diet (RD) sires and kept on the same diet throughout pregnancy and lactation. At weaning, offspring were maintained on either HCD or RD for 3 months resulting in 4 treatment groups that underwent cardiometabolic assessments. DNA and RNA were extracted from the hypothalamus to perform whole genome methylation, mRNA, and miRNA sequencing followed by bioinformatic analyses.
Maternal programming resulted in male-specific hypertension and hyperglycemia, with both males and females showing increased sympathetic tone to the vasculature. Surprisingly, programmed male offspring fed HCD in adulthood exhibited lower glucose levels, less insulin resistance, and leptin levels compared to non-programmed HCD-fed male mice. Hypothalamic genes involved in inflammation and type 2 diabetes were targeted by differentially expressed miRNA, while genes involved in glial and astrocytic differentiation were differentially methylated in programmed male offspring. These data were supported by our findings of astrogliosis, microgliosis and increased microglial activation in programmed males in the paraventricular nucleus (PVN). Programming induced a protective effect in male mice fed HCD in adulthood, resulting in lower protein levels of hypothalamic TGFβ2, NF-κB2, NF-κBp65, Ser-pIRS1, and GLP1R compared to non-programmed HCD-fed males. Although TGFβ2 was upregulated in male mice exposed to HCD pre- or post-natally, only blockade of the brain TGFβ receptor in RD-HCD mice improved glucose tolerance and a trend to weight loss.
Our study shows that maternal HCD programs neuronal plasticity in the offspring and results in male-specific hypertension and hyperglycemia associated with hypothalamic inflammation in mechanisms and pathways distinct from post-natal HCD exposure. Together, our data unmask a compensatory role of HCD programming, likely via priming of metabolic pathways to handle excess nutrients in a more efficient way.
Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance
2023, Cell Metabolism
Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKβ deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-κB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents. Microglial regulation of glucose homeostasis involves a tumor necrosis factor alpha (TNF-α)-dependent mechanism that increases activation of pro-opiomelanocortin (POMC) and other hypothalamic glucose-sensing neurons, ultimately leading to a marked amplification of first-phase insulin secretion via a parasympathetic pathway. Overall, these data indicate that microglia regulate glucose homeostasis in a body-weight-independent manner, an unexpected mechanism that limits the deterioration of glucose tolerance associated with obesity.
Fetal programming in sheep: Effects on pre- and postnatal organs and glands development in lambs
2022, Research in Veterinary Science
The present systematic review and meta-analysis aim to summarize the effects of maternal undernutrition or overnutrition during pregnancy on the absolute weight and relative weight of the organs (liver, kidneys, heart, spleen, and lung) and glands (adrenal, pancreas, and thyroid) measured during gestation, birth and the postnatal period in lambs. After completing the search, selection, and data extraction steps, the measure of effect was generated by the individual comparison of each variable response compared with the average of the control and treated group (undernutrition or overnutrition) using the DerSimonian and Laird method for random effects. The liver was the organ most affected by maternal undernutrition, as the absolute weight of the liver was reduced during pregnancy, birth, and the postnatal period. The extent of this effect is related to the duration of the intervention. Reductions in the absolute fetal weight of the lungs and spleen have also been observed. No change in organs weight were observed when the results were expressed as relative weight. For overnutrition, the fetal weight of the liver was reduced to both absolute and relative values. In contrast, the relative weight of the kidneys has been increased. For the glands analyzed, no changes in weight were observed in either scenario (absolute or relative weight). Thus, the organs are more likely to suffer weight changes, especially during pregnancy, as a result of maternal nutrition. However, this change in organ weight seems to be closely related to the reduction in body weight of the progeny as a whole.
The intake of β-sitosterol partially counteracts metformin beneficial effects in diet-induced obese rats
2022, Journal of Functional Foods
Citation 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.
Despite the high coexistence of hyperlipidaemia and the prediabetes state, little is known about the effects of the β-sitosterol and metformin (MET) combination. This study aimed to evaluate the effects of low doses of MET (75 or 150 mg/kg bw; M75 or M150) on western-diet induced obese (WDIO) rats, in combination or not with β-sitosterol (176 mg/kg bw; SIT and N-SIT, respectively). The gains of body weight and body fat mass, calorie food intake and plasma leptin were reduced in M150 animals, both SIT and N-SIT groups. Only N-SIT animals showed that insulin levels and HOMA-IR were reduced in the M150 group. M150 group showed a tendency towards lower mRNA levels of Npy and increased Lepr mRNA levels in hypothalamus, but only in N-SIT animals. In conclusion, these results show that the co-administration of MET with β-sitosterol seems to neutralise part of the beneficial effects of MET in WDIO rats.
Ratiometric fluorometric and colorimetric dual-mode sensing of glucose based on gold-platinum bimetallic nanoclusters
2022, Microchemical Journal
The synthesis of highly sensitive and selective luminescent probes provides a vital and efficient approach for diagnosing and preventing clinical diseases. In this work, gold-platinum bimetallic nanoclusters (Au − PtNCs-GMP) were synthesized with guanosine monophosphate (GMP) as the capping agent, which possessed strong fluorescent emission at 418 nm, and also exhibited great peroxidase-like mimetic activity. Glucose can be catalyzed to generate H₂O₂ by glucose oxidase, in the presence of H₂O₂, o-phenylenediamine (OPD) regarded as a representative non-fluorescent substance was catalyzed by Au-PtNCs-GMP and produced fluorescent 2,3-diaminophenazine (DAP) with an emission wavelength of 560 nm. Furthermore, the colorless OPD was oxidized to yellow DAP with UV–vis absorption peak at 420 nm. The generation of DAP can efficiently quench the fluorescence signal of Au-PtNCs-GMP at 418 nm on account of inner filter effect (IFE). The decrease of Au-PtNCs-GMP fluorescence and the increase of DAP fluorescence made it possible to detect glucose via ratiometric fluorometric intensity. Thus, a ratiometric fluorescent and colorimetric dual-mode sensing was achieved for glucose detection. The linear ranges of ratiometric fluorescence method and colorimetric method toward glucose were in the range of 0.01–0.4 mM and 0.05–0.4 mM, with the low limits of detection (LOD) of 7 μM and 11 μM, respectively. In addition, this dual-mode sensing method can be used for detecting glucose concentration in real biological samples with satisfying results, which provided a valuable and reliable strategy for glucose-related detections.

View all citing articles on Scopus

View full text

Trends in Endocrinology & Metabolism

ReviewHypothalamic Control of Systemic Glucose Homeostasis: The Pancreas Connection

Highlights

Section snippets

Historical Essentials

Location of Glucose-Sensing Neurons

Hypothalamic Control of Hepatic Glucose Production (HGP)

Hypothalamic Control of Glucose Metabolism in Skeletal Muscle

Hypothalamic Control of Glucose Metabolism in Adipose Tissue

Hypothalamic Control of Pancreatic Function

Evidence for Central Control of Glucose Homeostasis in Humans

Concluding Remarks

Acknowledgments

Glossary

Cell Metab.

Cell Metab.

Cell Metab.

Cell

Metabolism

Cell

Cell Metab.

Neuron

Neuroimage

Pharmacol. Biochem. Behav.

Cell

Trends Endocrinol. Metab.

Cell Metab.

Cell Metab.

Cell Metab.

The glucostatic theory of regulation of food intake and the problem of obesity

Bull. New Engl. Med. Cent.

Reciprocal activities of the ventromedial and lateral hypothalamic areas of cats

Science

Activity of single neurons in the hypothalamic feeding centers: effect of glucose

Am. J. Physiol.

Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity

Dis. Model. Mech.

Hypothalamic glucose sensing: making ends meet

Front. Syst. Neurosci.

Recent advances in the cellular and molecular mechanisms of hypothalamic neuronal glucose detection

Front. Physiol.

Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons

Front. Neuroanal.

Systemic glucoregulation by glucose-sensing neurons in the ventromedial hypothalamic nucleus (VMH)

J. Endocr. Soc.

Reciprocal influences of the ventromedial and lateral hypothalamic nuclei on blood glucose level and liver glycogen content

Nature

Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K+ channels

Pflugers Arch.

Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons

Diabetes

AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

J. Clin. Invest.

Neuronal control of peripheral insulin sensitivity and glucose metabolism

Nat. Commun.

Central leptin acutely reverses diet-induced hepatic insulin resistance

Diabetes

Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo

Nat. Commun.

Interaction between the central and peripheral effects of insulin in controlling hepatic glucose metabolism in the conscious dog

Diabetes

Peripheral glucose homeostasis: does brain insulin matter?

J. Clin. Invest.

Control of hepatic glucose metabolism by islet and brain

Diabetes Obes. Metab.

Intracerebroventricular infusion of glucose, insulin, and the adenosine monophosphate-activated kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, controls muscle glycogen synthesis

Endocrinology

Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats

Diabetes

Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats

Diabetes

Distinct effects of leptin and a melanocortin receptor agonist injected into medial hypothalamic nuclei on glucose uptake in peripheral tissues

Diabetes

Activation of SF1 neurons in the ventromedial hypothalamus by DREADD technology increases insulin sensitivity in peripheral tissues

Diabetes

Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms

Nat. Med.

Differential activation of the sympathetic innervation of adipose tissues by melanocortin receptor stimulation

Endocrinology

The central melanocortin system directly controls peripheral lipid metabolism

Review
Hypothalamic Control of Systemic Glucose Homeostasis: The Pancreas Connection

Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K⁺ channels