CNS GNPDA2 Does Not Control Appetite, but Regulates Glucose Homeostasis

GNPDA2 has been associated with human obesity and type-2 diabetes by using a GWAS approach. GNPDA2 is an enzyme involved in the hexosamine biosynthesis pathway, which is known to be important for nutrient sensing in various organism. Its counter enzyme, GFAT, has previously been shown to be important to the development of insulin resistance in diabetes. The implication of GNPDA2 and GFAT in metabolism is scarce and the effect of both enzymes over appetite and glucose homeostasis is unknown.Aim: Identify the role of GNPDA2 and GFAT in nutrient sensing circuits of the CNS that are important for the regulation of both appetite and glucose homeostasis.Methods: Using Long Evans rats, we administered either a GNPDA2 or GFAT antagonist or vehicle in i3vt.Key Findings:GNPDA2 is highly expressed in hypothalamus and adipose tissue, followed by muscle and liver. GNPDA2 is expressed in different hypothalamic nuclei (ARC, DMH, LHA, PVN). GNPDA2 is downregulated in hypothalamus under diet-induced obesity (as previously described), but GFAT expression does not change. Moreover, i3vt infusion of GNPDA2 or GFAT inhibitor resulted in increased c-Fos in areas related to appetite and glucose homeostasis control as PVN and DMH and to a lesser extent in the LHA and ARC. Central inhibition of GNPDA2 does not alter either acute food intake or body weight; however, GFAT inhibition diminished appetite and body weight due to visceral illness. In addition, central administration of the GNPDA2 antagonist, prior to an intraperitoneal glucose tolerance test, resulted in glucose intolerance in comparison to vehicle without altering insulin levels.Significance: These results suggest that central GNPDA2 does not control appetite, but regulates glucose homeostasis.

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Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00198.2011 ◽

2012 ◽

Vol 302 (8) ◽

pp. E924-E931 ◽

Cited By ~ 19

Author(s):

Toru Kusakabe ◽

Ken Ebihara ◽

Takeru Sakai ◽

Licht Miyamoto ◽

Daisuke Aotani ◽

...

Keyword(s):

Body Weight ◽

Insulin Sensitivity ◽

Food Intake ◽

Calorie Restriction ◽

Tolerance Test ◽

Body Weight Reduction ◽

Glucose Levels ◽

Diet Induced Obesity ◽

Antidiabetic Treatment ◽

Triglyceride Content

Leptin enhances insulin sensitivity in addition to reducing food intake and body weight. Recently, amylin, a pancreatic β-cell-derived hormone, was shown to restore a weight-reducing effect of leptin in leptin-resistant diet-induced obesity. However, whether amylin improves the effect of leptin on insulin sensitivity in diet-induced obesity is unclear. Diet-induced obese (DIO) mice were infused with either saline (S), leptin (L; 500 μg·kg−1·day−1), amylin (A; 100 μg·kg−1·day−1), or leptin plus amylin (L/A) for 14 days using osmotic minipumps. Food intake, body weight, metabolic parameters, tissue triglyceride content, and AMP-activated protein kinase (AMPK) activity were examined. Pair-feeding and weight-matched calorie restriction experiments were performed to assess the influence of food intake and body weight reduction. Continuous L/A coadministration significantly reduced food intake, increased energy expenditure, and reduced body weight, whereas administration of L or A alone had no effects. L/A coadministration did not affect blood glucose levels during ad libitum feeding but decreased plasma insulin levels significantly (by 48%), suggesting the enhancement of insulin sensitivity. Insulin tolerance test actually showed the increased effect of insulin in L/A-treated mice. In addition, L/A coadministration significantly decreased tissue triglyceride content and increased AMPKα2 activity in skeletal muscle (by 67%). L/A coadministration enhanced insulin sensitivity more than pair-feeding and weight-matched calorie restriction. In conclusion, this study demonstrates the beneficial effect of L/A coadministration on glucose and lipid metabolism in DIO mice, indicating the possible clinical usefulness of L/A coadministration as a new antidiabetic treatment in obesity-associated diabetes.

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Evidence and manipulation of O-GlcNAcylation in granulosa cells of bovine antral follicles†

Biology of Reproduction ◽

10.1093/biolre/ioab013 ◽

2021 ◽

Vol 104 (4) ◽

pp. 914-923

Author(s):

Abigail M Maucieri ◽

David H Townson

Keyword(s):

Granulosa Cells ◽

Follicular Fluid ◽

Nutrient Sensing ◽

Direct Inhibition ◽

Antral Follicles ◽

Cellular Processes ◽

Hexosamine Biosynthesis ◽

Follicle Size ◽

Glcnac Transferase ◽

Hexosamine Biosynthesis Pathway

Abstract Glucose is a preferred energy substrate for metabolism by bovine granulosa cells (GCs). O-linked N-acetylglucosaminylation (O-GlcNAcylation), is a product of glucose metabolism that occurs as the hexosamine biosynthesis pathway (HBP) shunts O-GlcNAc sugars to serine and threonine residues of proteins. O-GlcNAcylation through the HBP is considered a nutrient sensing mechanism that regulates many cellular processes. Yet little is known of its importance in GCs. Here, O-GlcNAcylation in GCs and its effects on GC proliferation were determined. Bovine ovaries from a slaughterhouse, staged to the mid-to-late estrous period were used. Follicular fluid and GCs were aspirated from small (3–5 mm) and large (>10 mm) antral follicles. Freshly isolated GCs of small follicles exhibited greater expression of O-GlcNAcylation and O-GlcNAc transferase (OGT) than large follicles. Less glucose and more lactate was detectable in the follicular fluid of small versus large follicles. Culture of GCs revealed that inhibition of the HBP via the glutamine fructose-6-phosphate aminotransferase inhibitor, DON (50 μM), impaired O-GlcNAcylation and GC proliferation, regardless of follicle size. Direct inhibition of O-GlcNAcylation via the OGT inhibitor, OSMI-1 (50 μM), also prevented proliferation, but only in GCs of small follicles. Augmentation of O-GlcNAcylation via the O-GlcNAcase inhibitor, Thiamet-G (2.5 μM), had no effect on GC proliferation, regardless of follicle size. The results indicate GCs of bovine antral follicles undergo O-GlcNAcylation, and O-GlcNAcylation is associated with alterations of glucose and lactate in follicular fluid. Disruption of O-GlcNAcylation impairs GC proliferation. Thus, the HBP via O-GlcNAcylation constitutes a plausible nutrient-sensing pathway influencing bovine GC function and follicular growth.

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N-Glycan Remodeling on Glucagon Receptor Is an Effector of Nutrient Sensing by the Hexosamine Biosynthesis Pathway

Journal of Biological Chemistry ◽

10.1074/jbc.m114.563734 ◽

2014 ◽

Vol 289 (23) ◽

pp. 15927-15941 ◽

Cited By ~ 29

Author(s):

Anita Johswich ◽

Christine Longuet ◽

Judy Pawling ◽

Anas Abdel Rahman ◽

Michael Ryczko ◽

...

Keyword(s):

Nutrient Sensing ◽

Biosynthesis Pathway ◽

Glucagon Receptor ◽

Hexosamine Biosynthesis ◽

Hexosamine Biosynthesis Pathway

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Endogenous VMH amylin signaling is required for full leptin signaling and protection from diet-induced obesity

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00462.2015 ◽

2016 ◽

Vol 310 (4) ◽

pp. R355-R365 ◽

Cited By ~ 21

Author(s):

Ambrose A. Dunn-Meynell ◽

Christelle Le Foll ◽

Miranda D. Johnson ◽

Thomas A. Lutz ◽

Matthew R. Hayes ◽

...

Keyword(s):

Ventromedial Hypothalamus ◽

Tolerance Test ◽

Leptin Resistance ◽

Oral Glucose ◽

Dorsomedial Nucleus ◽

Adeno Associated Virus ◽

Leptin Signaling ◽

Insulin Resistant ◽

Diet Induced Obesity ◽

Hypothalamic Nuclei

Amylin enhances arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei leptin signaling and synergistically reduces food intake and body weight in selectively bred diet-induced obese (DIO) rats. Since DIO 125I-amylin dorsomedial nucleus-dorsomedial VMN binding was reduced, we postulated that this contributed to DIO ventromedial hypothalamus (VMH) leptin resistance, and that impairing VMH (ARC + VMN) calcitonin receptor (CTR)-mediated signaling by injecting adeno-associated virus (AAV) expressing a short hairpin portion of the CTR mRNA would predispose diet-resistant (DR) rats to obesity on high-fat (45%) diet (HFD). Depleting VMH CTR by 80–90% in 4-wk-old male DR rats reduced their ARC and VMN 125I-labeled leptin binding by 57 and 51%, respectively, and VMN leptin-induced phospho-signal transducer and activator of transcription 3-positive neurons by 59% vs. AAV control rats. After 6 wk on chow, VMH CTR-depleted DR rats ate and gained the equivalent amount of food and weight but had 18% heavier fat pads (relative to carcass weight), 144% higher leptin levels, and were insulin resistant compared with control AAV DR rats. After 6 wk more on HFD, VMH CTR-depleted DR rats ate the same amount but gained 28% more weight, had 60% more carcass fat, 254% higher leptin levels, and 132% higher insulin areas under the curve during an oral glucose tolerance test than control DR rats. Therefore, impairing endogenous VMH CTR-mediated signaling reduced leptin signaling and caused DR rats to become more obese and insulin resistant, both on chow and HFD. These results suggest that endogenous VMH amylin signaling is required for full leptin signaling and protection from HFD-induced obesity.

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Central Sirt1 Regulates Body Weight and Energy Expenditure Along With the POMC-Derived Peptide α-MSH and the Processing Enzyme CPE Production in Diet-Induced Obese Male Rats

Endocrinology ◽

10.1210/en.2014-1970 ◽

2015 ◽

Vol 156 (3) ◽

pp. 961-974 ◽

Cited By ~ 14

Author(s):

Nicole E. Cyr ◽

Jennifer S. Steger ◽

Anika M. Toorie ◽

Jonathan Z. Yang ◽

Ronald Stuart ◽

...

Keyword(s):

Body Weight ◽

Energy Balance ◽

Energy Expenditure ◽

Obese Individual ◽

Nutrient Sensing ◽

Sirtuin 1 ◽

Male Rats ◽

Sprague Dawley ◽

Phosphorylated Akt ◽

Central Inhibition

Abstract In the periphery, the nutrient-sensing enzyme Sirtuin 1 (silent mating type information regulation 2 homolog 1 [Sirt1]) reduces body weight in diet-induced obese (DIO) rodents. However, the role of hypothalamic Sirt1 in body weight and energy balance regulation is debated. The first studies to reveal that central Sirt1 regulates body weight came from experiments in our laboratory using Sprague-Dawley rats. Central inhibition of Sirt1 decreased body weight and food intake as a result of a forkhead box protein O1 (FoxO1)-mediated increase in the anorexigenic proopiomelanocortin (POMC) and decrease in the orexigenic Agouti-related peptide in the hypothalamic arcuate nucleus. Here, we demonstrate that central inhibition of Sirt1 in DIO decreased body weight and increased energy expenditure at higher levels as compared with the lean counterpart. Brain Sirt1 inhibition in DIO increased acetylated FoxO1, which in turn increased phosphorylated FoxO1 via improved insulin/phosphorylated AKT signaling. Elevated acetylated FoxO1 and phosphorylated FoxO1 increased POMC along with the α-melanocyte-stimulating hormone (α-MSH) maturation enzyme carboxypeptidase E, which resulted in more of the bioactive POMC product α-MSH released into the paraventricular nucleus. Increased in α-MSH led to augmented TRH levels and circulating T3 levels (triiodothyronine, thyroid hormone). These results indicate that inhibiting hypothalamic Sirt1 in DIO enhances the activity of the hypothalamic-pituitary-thyroid axis, which stimulates energy expenditure. Because we show that blocking central Sirt1 causes physiological changes that promote a negative energy balance in an obese individual, our results support brain Sirt1 as a significant target for weight loss therapeutics.

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Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00186.2003 ◽

2003 ◽

Vol 285 (5) ◽

pp. E949-E957 ◽

Cited By ~ 84

Author(s):

Barry E. Levin ◽

Ambrose A. Dunn-Meynell ◽

Matt R. Ricci ◽

David E. Cummings

Keyword(s):

Body Weight ◽

Mrna Expression ◽

Leptin Receptor ◽

High Energy ◽

Proximate Cause ◽

Ghrelin Receptor ◽

Insulin Levels ◽

Diet Induced Obesity ◽

Leptin Sensitivity ◽

Hypothalamic Nuclei

Rats selectively bred to develop diet-induced obesity (DIO) spontaneously gain more body weight between 5 and 7 wk of age than do those bred to be diet resistant (DR). Here, chow-fed DIO rats ate 9% more and gained 19% more body weight from 5 to 6 wk of age than did DR rats but had comparable leptin and insulin levels. However, 6-wk-old DIO rats had 29% lower plasma ghrelin levels at dark onset but equivalent levels 6 h later compared with DR rats. When subsequently fed a high-energy (HE; 31% fat) diet for 10 days, DIO rats ate 70% more, gained more body and adipose depot weight, had higher leptin and insulin levels, and had 22% lower feed efficiency than DR rats fed HE diet. In DIO rats on HE diet, leptin levels increased significantly at 3 days followed by increased insulin levels at 7 days. These altered DIO leptin and ghrelin responses were associated with 10% lower leptin receptor mRNA expression in the arcuate (ARC), dorsomedial (DMN), and ventromedial hypothalamic nuclei and 13 and 15% lower ghrelin receptor (GHS-R) mRNA expression in the ARC and DMN than in the DR rats. These data suggest that increased ghrelin signaling is not a proximate cause of DIO, whereas reduced leptin sensitivity might play a causal role.

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The role of nutrient sensing in the metabolic changes after gastric bypass surgery

Journal of Endocrinology ◽

10.1530/joe-16-0541 ◽

2017 ◽

Vol 232 (3) ◽

pp. 363-376 ◽

Cited By ~ 7

Author(s):

Sandra Steensels ◽

Matthias Lannoo ◽

Bert Avau ◽

Jorien Laermans ◽

Laurien Vancleef ◽

...

Keyword(s):

Gastric Bypass ◽

Body Weight ◽

Glucose Homeostasis ◽

Glucose Transporter ◽

Nutrient Sensing ◽

Dependent Manner ◽

Hormone Release ◽

L Cell ◽

Gut Hormone

Taste receptors coupled to the gustatory G-protein, gustducin, on enteroendocrine cells sense nutrients to regulate gut hormone release. During Roux-en-Y gastric bypass (RYGB) surgery, the altered nutrient flow to more distal regions can affect gustducin-mediated gut hormone release and hence energy and glucose homeostasis. We studied the role of gustducin-mediated signaling in the metabolic improvements and intestinal adaptations along the gut after RYGB surgery in wild-type (WT) and α-gustducin−/− (α-gust−/−) mice. RYGB surgery decreased body weight in WT and α-gust−/− mice, whereas food intake was only decreased in WT mice. Pair-feeding to the RYGB group improved glucose homeostasis to a similar extent in WT mice. GLP1 levels were increased in both genotypes, PYY levels in α-gust−/− mice and octanoyl ghrelin levels were not affected after RYGB surgery. In WT mice, nutrients act via α-gustducin to increase L-cell differentiation (foregut) and L-cell number (foregut and hindgut) in a region-dependent manner. In α-gust−/− mice, the effect on gut hormone levels is probably tuned via increased peptide sensor and glucose transporter expression in the Roux limb and increased caecal butyrate and propionate levels in the hindgut that activate free fatty acid receptors. Finally, signaling via α-gustducin plays a role in the increased ion transport of the foregut but not in the improvement in colonic barrier function. In conclusion, RYGB surgery decreased body weight in both WT and α-gust−/− mice. Elevated plasma GLP1 and PYY levels might mediate this effect, although α-gustducin differentially affects several regulatory systems in the foregut and hindgut, tuning gut hormone release.

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Central Administration of 1-Deoxynojirimycin Attenuates Hypothalamic Endoplasmic Reticulum Stress and Regulates Food Intake and Body Weight in Mice with High-Fat Diet-Induced Obesity

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/3607089 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Jongwan Kim ◽

Eun-Young Yun ◽

Fu-Shi Quan ◽

Seung-Won Park ◽

Tae-Won Goo

Keyword(s):

Body Weight ◽

Er Stress ◽

High Fat Diet ◽

Central Administration ◽

High Fat ◽

Signal Transducers ◽

Diet Induced Obesity ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

The Central Nervous System

Theα-glucosidase inhibitor, 1-deoxynojirimycin (DNJ), is widely used for its antiobesity and antidiabetic effects. Researchers have demonstrated that DNJ regulates body weight by increasing adiponectin levels, which affects energy intake and prevents diet-induced obesity. However, the mechanism by which centrally administered DNJ exerts anorexigenic effects has not been studied until now. We investigated the effect of DNJ in the hypothalamus of mice with high-fat diet-induced obesity. Results showed that intracerebroventricular (ICV) administration of DNJ reduced hypothalamic ER stress, which activated the leptin-induced Janus-activated kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) signaling pathway to cause appetite suppression. We conclude that DNJ may reduce obesity by moderating feeding behavior and ER stress in the hypothalamic portion of the central nervous system (CNS).

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Disruption of the sugar-sensing receptor T1R2 attenuates metabolic derangements associated with diet-induced obesity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00484.2015 ◽

2016 ◽

Vol 310 (8) ◽

pp. E688-E698 ◽

Cited By ~ 17

Author(s):

Kathleen R. Smith ◽

Tania Hussain ◽

Elnaz Karimian Azari ◽

Jennifer L. Steiner ◽

Julio E. Ayala ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Balance ◽

Fat Mass ◽

Glucose Homeostasis ◽

Sweet Taste ◽

Nutrient Sensing ◽

Whole Body ◽

Receptor Protein ◽

Peripheral Tissues ◽

Diet Induced Obesity

Sweet taste receptors (STRs) on the tongue mediate gustatory sweet sensing, but their expression in the gut, pancreas, and adipose tissue suggests a physiological contribution to whole body nutrient sensing and metabolism. However, little is known about the function and contribution of these sugar sensors during metabolic stress induced by overnutrition and subsequent obesity. Here, we investigated the effects of high-fat/low-carbohydrate (HF/LC) diet on glucose homeostasis and energy balance in mice with global disruption of the sweet taste receptor protein T1R2. We assessed body composition, energy balance, glucose homeostasis, and tissue-specific nutrient metabolism in T1R2 knockout (T1R2-KO) mice fed a HF/LC diet for 12 wk. HF/LC diet-fed T1R2-KO mice gained a similar amount of body mass as did WT mice, but had reduced fat mass and increased lean mass relative to WT mice. T1R2-KO mice were also hyperphagic and hyperactive. Ablation of the T1R2 sugar sensor protected mice from HF/LC diet-induced hyperinsulinemia and altered substrate utilization, including increased rates of glucose oxidation and decreased liver triglyceride (TG) accumulation, despite normal intestinal fat absorption. Finally, STRs ( T1r2/T1r3) were upregulated in the adipose tissue of WT mice in response to HF/LC diet, and their expression positively correlated with fat mass and glucose intolerance. The chemosensory receptor T1R2, plays an important role in glucose homeostasis during diet-induced obesity through the regulation of yet to be identified molecular mechanisms that alter energy disposal and utilization in peripheral tissues.

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