Leptin Action in the Ventromedial Hypothalamic Nucleus Is Sufficient, But Not Necessary, to Normalize Diabetic Hyperglycemia

In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's antidiabetic effects because leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus. This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production and plasma glucagon levels but had no effect on tissue glucose uptake in the skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine whether VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for the correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's antidiabetic action but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.

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Hypothalamic Leptin Signaling Regulates Hepatic Insulin Sensitivity via a Neurocircuit Involving the Vagus Nerve

Endocrinology ◽

10.1210/en.2009-0445 ◽

2009 ◽

Vol 150 (10) ◽

pp. 4502-4511 ◽

Cited By ~ 111

Author(s):

Jonathan German ◽

Francis Kim ◽

Gary J. Schwartz ◽

Peter J. Havel ◽

Christopher J. Rhodes ◽

...

Keyword(s):

Insulin Sensitivity ◽

Vagus Nerve ◽

Leptin Receptor ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Insulin Sensitivity ◽

Leptin Signaling ◽

Peripheral Insulin Sensitivity ◽

Hepatic Expression ◽

Beneficial Effects

Abstract Recent evidence suggests that hormones such as insulin and leptin act in the hypothalamus to regulate energy balance and glucose metabolism. Here we show that in leptin receptor-deficient Koletsky (fak/fak) rats, adenovirally induced expression of leptin receptors in the area of the hypothalamic arcuate nucleus improved peripheral insulin sensitivity via enhanced suppression of hepatic glucose production, with no change of insulin-stimulated glucose uptake or disposal. This effect was associated with increased insulin signal transduction via phosphatidylinositol-3-OH kinase (as measured by pY-insulin receptor substrate-1 and pS-PKB/Akt) in liver, but not skeletal muscle, and with reduced hepatic expression of the gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate kinase. Moreover, the beneficial effects of hypothalamic leptin signaling on hepatic insulin sensitivity were blocked by selective hepatic vagotomy. We conclude that hypothalamic leptin action increases peripheral insulin sensitivity primarily via effects on the liver and that the mechanism underlying this effect is dependent on the hepatic branch of the vagus nerve.

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Identification of a discrete neuronal circuit that relays insulin signaling into the brain to regulate glucose homeostasis

10.1101/2021.09.13.460055 ◽

2021 ◽

Author(s):

Mouna El Mehdi ◽

Saloua Takhlidjt ◽

Mélodie Devère ◽

Arnaud Arabo ◽

Marie-Anne Le Solliec ◽

...

Keyword(s):

Glucose Homeostasis ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Inhibitory Effect ◽

Neuronal Population ◽

Biologically Active ◽

Hypothalamic Nucleus ◽

Hypothalamic Area ◽

Antihyperglycemic Effect ◽

Hypothalamic Regulation

26RFa (QRFP) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localized in the hypothalamus. In the present study, we have investigated whether the 26RFa neurons may be involved in the hypothalamic regulation of glucose homeostasis. Our data indicate that 26RFa, i.c.v. injected, induces a robust antihyperglycemic effect associated with an increase of insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26RFa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26RFa in the lateral hypothalamic area and the ventromedial hypothalamic nucleus also express the insulin receptor and that insulin induces the expression of 26RFa in these neurons. Concurrently, we show that the central antihyperglycemic effect of insulin is abolished in presence of a 26RFa receptor (GPR103) antagonist as well as in mice deficient for 26RFa. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production. To conclude, in the present study we have identified a novel actor of the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system and we provide the evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.

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P0950EFFECT OF THYROID HORMONE TREATMENT ON RENAL REABSORPTION OF GLUCOSE IN ALLOXAN-INDUCED DIABETIC RATS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0950 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Gireesh Dayma

Keyword(s):

Blood Glucose ◽

Thyroid Hormone ◽

Glucose Homeostasis ◽

Hepatic Glucose Production ◽

Liver Perfusion ◽

Glucose Production ◽

Diabetic Rats ◽

Hepatic Glucose ◽

Glucose Output ◽

Renal Expression

Abstract Background and Aims The thyroid hormone (TH) plays an important role in glucose metabolism. Recently, we showed that the TH improves glycemia control by decreasing cytokines expression in the adipose tissue and skeletal muscle of alloxan-induced diabetic rats, which were also shown to present primary hypothyroidism. In this context, this study aims to investigate whether the chronic treatment of diabetic rats with T3 could affect other tissues that are involved in the control of glucose homeostasis, as the liver and kidney. Method Adult male Wistar rats were divided into nondiabetic, diabetic, and diabetic treated with T3 (1.5 ?g/100 g BW for 4 weeks). Diabetes was induced by alloxan monohydrate (150 mg/kg, BW, i.p.). Animals showing fasting blood glucose levels greater than 250 mg/dL were selected for the study. Results After treatment, we measured the blood glucose, serum T3, T4, TSH, and insulin concentration, hepatic glucose production by liver perfusion, liver PEPCK, GAPDH, and pAKT expression, as well as urine glucose concentration and renal expression of SGLT2 and GLUT2. T3 reduced blood glucose, hepatic glucose production, liver PEPCK, GAPDH, and pAKT content and the renal expression of SGLT2 and increased glycosuria. Conclusion Results suggest that the decreased hepatic glucose output and increased glucose excretion induced by T3 treatment are important mechanisms that contribute to reduce serum concentration of glucose, accounting for the improvement of glucose homeostasis control in diabetic rats.

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Glucagon Deficiency Reduces Hepatic Glucose Production and Improves Glucose Tolerance In Adult Mice

Endocrine Reviews ◽

10.1210/edrv.31.4.9983 ◽

2010 ◽

Vol 31 (4) ◽

pp. 606-606

Author(s):

Aidan S. Hancock ◽

Aiping Du ◽

Jingxuan Liu ◽

Mayumi Miller ◽

Catherine L. May

Keyword(s):

Glucose Homeostasis ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Postprandial Glucose ◽

Glucagon Receptor ◽

Glucose Levels ◽

Adult Mice ◽

Hepatic Glucose ◽

Knockout Animals

Abstract The major role of glucagon is to promote hepatic gluconeogenesis and glycogenolysis to raise blood glucose levels during hypoglycemic conditions. Several animal models have been established to examine the in vivo function of glucagon in the liver through attenuation of glucagon via glucagon receptor knockout animals and pharmacological interventions. To investigate the consequences of glucagon loss to hepatic glucose production and glucose homeostasis, we derived mice with a pancreas specific ablation of the α-cell transcription factor, Arx, resulting in a complete loss of the glucagon-producing pancreatic α-cell. Using this model, we found that glucagon is not required for the general health of mice but is essential for total hepatic glucose production. Our data clarifies the importance of glucagon during the regulation of fasting and postprandial glucose homeostasis.

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A critical view of the use of genetic tools to unveil neural circuits: the case of leptin action in reproduction

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00444.2013 ◽

2014 ◽

Vol 306 (1) ◽

pp. R1-R9 ◽

Cited By ~ 13

Author(s):

Carol F. Elias

Keyword(s):

Mouse Models ◽

Leptin Receptor ◽

Receptor Gene ◽

Pubertal Development ◽

Leptin Signaling ◽

Genetic Tools ◽

Virus Vectors ◽

Neuronal Populations ◽

Area Of Interest ◽

Neuroendocrine Axis

The remarkable development and refinement of the Cre-loxP system coupled with the nonstop production of new mouse models and virus vectors have impelled the growth of various fields of investigation. In this article, I will discuss the data collected using these genetic tools in our area of interest, giving specific emphasis to the identification of the neuronal populations that relay leptin action in reproductive physiology. A series of mouse models that allow manipulation of the leptin receptor gene have been generated. Of those, I will discuss the use of two models of leptin receptor gene reexpression ( LepR neo/neo and LepR loxTB/loxTB) and one model of leptin signaling blockade ( LepR flox/flox). I will also highlight the differences of using stereotaxic delivery of virus vectors expressing DNA-recombinases (Flp and Cre) and mouse models expressing Cre-recombinase. Our findings indicate that leptin action in the ventral premammillary nucleus is sufficient, but not required, for leptin action in reproduction and that leptin action in Kiss1 neurons arises after pubertal maturation; therefore, direct leptin signaling in Kiss1 neurons is neither required nor sufficient for the permissive action of leptin in pubertal development. It also became evident that the full action of leptin in the reproductive neuroendocrine axis requires the engagement of an integrated circuitry, yet to be fully unveiled.

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Prevention of Diabetes in db/db Mice by Dietary Soy Is Independent of Isoflavone Levels

Endocrinology ◽

10.1210/en.2012-1490 ◽

2012 ◽

Vol 153 (11) ◽

pp. 5200-5211 ◽

Cited By ~ 19

Author(s):

Céline Zimmermann ◽

Christopher R. Cederroth ◽

Lucie Bourgoin ◽

Michelangelo Foti ◽

Serge Nef

Keyword(s):

Glucose Homeostasis ◽

Cell Function ◽

Hepatic Glucose Production ◽

Cell Mass ◽

Glucose Production ◽

Metabolic Effects ◽

Pancreatic Β Cell ◽

Β Cell ◽

Glucose Levels ◽

Hepatic Glucose

Abstract Recent evidence points towards the beneficial use of soy proteins and isoflavones to improve glucose control and slow the progression of type 2 diabetes. Here, we used diabetic db/db mice fed a high soy-containing diet (SD) or a casein soy-free diet to investigate the metabolic effects of soy and isoflavones consumption on glucose homeostasis, hepatic glucose production, and pancreatic islet function. Male db/db mice fed with a SD exhibited a robust reduction in hyperglycemia (50%), correlating with a reduction in hepatic glucose production and preserved pancreatic β-cell function. The rapid decrease in fasting glucose levels resulted from an inhibition of gluconeogenesis and an increase in glycolysis in the liver of db/db mice. Soy consumption also prevented the loss of pancreatic β-cell mass and thus improved glucose-stimulated insulin secretion (3-fold), which partly accounted for the overall improvements in glucose homeostasis. Comparison of SD effects on hyperglycemia with differing levels of isoflavones or with purified isoflavones indicate that the beneficial physiological effects of soy are not related to differences in their isoflavone content. Overall, these findings suggest that consumption of soy is beneficial for improving glucose homeostasis and delaying the progression of diabetes in the db/db mice but act independently of isoflavone concentration.

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LEPTIN RESISTANCE AND TYPE 2 DIABETES

International Journal of Medicine and Medical Research ◽

10.11603/ijmmr.2413-6077.2017.1.7563 ◽

2017 ◽

Author(s):

O. M. Oleshchuk ◽

H. Ya. Loi

Keyword(s):

Type 2 Diabetes ◽

Leptin Receptor ◽

Hepatic Glucose Production ◽

Glucose Production ◽

The Body ◽

Leptin Resistance ◽

Pharmacologic Agent ◽

Genes Encoding ◽

The Status

Leptin is one of adipocyte-secreted hormones. It signals to the brain and other tissues about the status of body energy reserves. Circulating leptin levels are directly proportional to the amount of the body fat. Leptin concentration increases when surfeit and decreases during fasting. Obese patients are hyperleptinemic compared with thin persons and they are tolerant to the central hypothalamic effects of leptin. The reduced sensitivity toward exogenous and endogenous leptin is commonly referred to as leptin resistance. Alterations in the signaling of the long isoform of the leptin receptor play the crucial role in leptin resistance. Surfeit may induce leptin resistance and other metabolic sequelae of obesity. Leptin insensitivity and insulin resistance play a major role in the development of type 2 diabetes. Metformin remains the preferred first-line pharmacologic agent for the treatment of type 2 diabetes. It reduces hepatic glucose production, increases glucose uptake in peripheral tissue and can lead to weight loss. Metformin decreases both insulin and leptin concentration, restores the sensitivity to these hormones. But some studies have shown poor relationship between metformin action and leptin level. And the mechanism of metformin action on leptin resistance remains unclear. Thus, these issues should be studied as well as polymorphisms in genes encoding metformin action.

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Abstract 25: Angiotensin AT 1A Receptors on Leptin Receptor-Expressing Cells are Required for the Blood Pressure and Metabolic Rate Effects of Leptin

Hypertension ◽

10.1161/hyp.62.suppl_1.a25 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Justin L Grobe ◽

Kristin E Claflin

Keyword(s):

Blood Pressure ◽

Metabolic Rate ◽

Body Mass ◽

Leptin Receptor ◽

Receptor Gene ◽

Brain Regions ◽

Leptin Resistance ◽

Brown Adipose ◽

Obesity Hypertension ◽

The Brain

Circulating leptin and the local brain renin-angiotensin system (RAS) both contribute to the control of food intake (FI), resting metabolic rate (RMR) and blood pressure (BP), and both have been postulated to contribute to obesity-hypertension. Here we examined the provocative hypothesis that the brain RAS is required for (or mediates) the RMR- and BP-stimulating effects of leptin. To create animals lacking the AT 1A receptor specifically in cells expressing the leptin receptor (“KO”), mice with a flox’ed version of the endogenous angiotensin AT 1A receptor gene (AT 1A flox ) were crossed with mice expressing cre-recombinase via the leptin receptor promoter (ObR-Cre). Body mass, body composition, blood chemistry, glucose tolerance, and FI behaviors were essentially unchanged through 34 weeks of age in mice maintained on standard chow (Teklad 7013). In contrast, anesthetized BP (MAP; control n=9, 91.6 ± 4.1, vs KO n=8, 78.0 ± 3.7 mmHg) and heart rate (351 ± 13, vs 308 ± 11 BPM) were reduced in KO mice (both P<0.05). Further, interscapular brown adipose (BAT SNA, 112 ± 22, vs 22 ± 35 % above baseline at 3 hr) and renal (154 ± 19, vs 53 ± 23 % above baseline at 3 hr) sympathetic nerve activity responses to acute leptin injection (60 μg, i.v.) were completely abolished (both P<0.05). When maintained on a 45% high fat diet (OpenSource D12451 ) to increase endogenous leptin production, KO mice exhibited accelerated body mass (control n=15, -0.1 ± 0.1, vs KO n=4, +1.7 ± 0.5 g/wk) and fat mass (+2.9 ± 0.5, vs +4.9 ± 1.1 g/5 wk) gains (both P<0.05), likely due to normal FI behaviors but a 18% reduction in RMR (control n=16, 0.196 ± 0.011, vs KO n=7, 0.161 ± 0.004 kcal/hr at 30°C, P<0.05). We conclude that expression of angiotensin AT 1A receptors on leptin-sensitive cells is required for the metabolic rate and cardiovascular effects of leptin. Ongoing studies are focused on identifying the brain regions and subsets of leptin receptor-expressing cells in which this RAS-leptin cross-talk occurs, and the directionality and molecular mediators of this interaction. We hypothesize that uncontrolled or pathological activity of the brain RAS may thus help explain the clinically variable effects of leptin, and contribute to the mechanism(s) of selective leptin resistance and obesity-hypertension.

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Glucose production during exercise in humans: a-hv balance and isotopic-tracer measurements compared

Journal of Applied Physiology ◽

10.1152/jappl.1999.87.1.111 ◽

1999 ◽

Vol 87 (1) ◽

pp. 111-115 ◽

Cited By ~ 17

Author(s):

R. Bergeron ◽

M. Kjaer ◽

L. Simonsen ◽

J. Bülow ◽

H. Galbo

Keyword(s):

Blood Flow ◽

Continuous Infusion ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Splanchnic Blood Flow ◽

Dilution Method ◽

Hepatic Glucose ◽

Balance Technique ◽

Tracer Dilution ◽

Exercise In Humans

The present study compared the arteriohepatic venous (a-hv) balance technique and the tracer-dilution method for estimation of hepatic glucose production during both moderate and heavy exercise in humans. Eight healthy young men (aged 25 yr; range, 23–30 yr) performed semisupine cycling for 40 min at 50.4 ± 1.5(SE)% maximal O2 consumption, followed by 30 min at 69.0 ± 2.2% maximal O2 consumption. The splanchnic blood flow was estimated by continuous infusion of indocyanine green, and net splanchnic glucose output was calculated as the product of splanchnic blood flow and a-hv blood glucose concentration differences. Glucose appearance rate was determined by a primed, continuous infusion of [3-3H]glucose and was calculated by using formulas for a modified single compartment in non-steady state. Glucose production was similar whether determined by the a-hv balance technique or by the tracer-dilution method, both at rest and during moderate and intense exercise ( P > 0.05). It is concluded that, during exercise in humans, determination of hepatic glucose production can be performed equally well with the two techniques.

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