scholarly journals Overexpression of the Gene Encoding Neurosecretory Protein GL Precursor Prevents Excessive Fat Accumulation in the Adipose Tissue of Mice Fed a Long-Term High-Fat Diet

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6006
Author(s):  
Keisuke Fukumura ◽  
Yuki Narimatsu ◽  
Shogo Moriwaki ◽  
Eiko Iwakoshi-Ukena ◽  
Megumi Furumitsu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Feeding Behavior ◽  
High Fat Diet ◽  
Oral Glucose ◽  
High Fat ◽  
Gene Encoding ◽  
Fat Accumulation ◽  
Insulin Tolerance

We previously identified a novel small hypothalamic protein, neurosecretory protein GL (NPGL), which induces feeding behavior and fat accumulation in rodents depending on their diet. In the present study, we explored the effects of NPGL on feeding behavior and energy metabolism in mice placed on a long-term high-fat diet with 60% calories from fat (HFD 60). Overexpression of the NPGL precursor gene (Npgl) over 18 weeks increased food intake and weight. The weekly weight gain of Npgl-overexpressing mice was higher than that of controls until 7 weeks from induction of overexpression, after which it ceased to be so. Oral glucose tolerance tests showed that Npgl overexpression maintained glucose tolerance and increased blood insulin levels, and intraperitoneal insulin tolerance tests showed that it maintained insulin sensitivity. At the experimental endpoint, Npgl overexpression was associated with increased mass of the perirenal white adipose tissue (WAT) and decreased mass of the epididymal WAT (eWAT), resulting in little effect on the total WAT mass. These results suggest that under long-term HFD 60 feeding, Npgl overexpression may play a role in avoiding metabolic disturbance both by accelerating energy storage and by suppressing excess fat accumulation in certain tissues, such as the eWAT.

scholarly journals Overexpression of the gene encoding neurosecretory protein GL precursor prevents excessive fat accumulation in the adipose tissue of mice fed a long-term high-fat diet

2021 ◽  
Author(s):  
Keisuke Fukumura ◽  
Yuki Narimatsu ◽  
Shogo Moriwaki ◽  
Eiko Iwakoshi-Ukena ◽  
Megumi Furumitsu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Feeding Behavior ◽  
Body Mass ◽  
High Fat Diet ◽  
Mass Gain ◽  
Oral Glucose ◽  
High Fat ◽  
Fat Accumulation

We previously identified a novel small hypothalamic protein, neurosecretory protein GL (NPGL), which induces feeding behavior and fat accumulation in rodents depending on their diet. In the present study, we explored the effects of NPGL on feeding behavior and energy metabolism in mice placed on a long-term high-fat diet with 60% calories from fat (HFD 60). Overexpression of the NPGL precursor gene (Npgl) over 18 weeks increased food intake and body mass. The weekly body mass gain of Npgl-overexpressing mice was higher than that of controls until 7 weeks from induction of overexpression, after which it ceased to be so. Oral glucose tolerance tests showed that Npgl overexpression maintained glucose tolerance and increased blood insulin levels, and intraperitoneal insulin tolerance tests showed that it maintained insulin sensitivity. At the experimental endpoint, Npgl overexpression was associated with increased mass of the perirenal white adipose tissue (WAT) and decreased mass of the epididymal WAT (eWAT), resulting in little effect on the total WAT mass. These results suggest that under long-term HFD 60 feeding, Npgl overexpression may play a role in avoiding metabolic disturbance both by accelerating energy storage and by suppressing excess fat accumulation in certain tissues, such as the eWAT.

scholarly journals Resolution of glucose intolerance in long-term high-fat, high-sucrose-fed mice

2017 ◽  
Vol 233 (3) ◽  
pp. 269-279 ◽  
Author(s):  
Greg M Kowalski ◽  
Michael J Kraakman ◽  
Shaun A Mason ◽  
Andrew J Murphy ◽  
Clinton R Bruce
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Glucose Intolerance ◽  
Subcutaneous Adipose Tissue ◽  
Glucose Disposal ◽  
Oral Glucose ◽  
High Fat ◽  
Subcutaneous Adipose ◽  
High Sucrose

The high-fat, high-sucrose diet (HFSD)–fed C57Bl/6 mouse is a widely used model of prediabetes. However, studies typically implement a relatively short dietary intervention lasting between 4 and 16 weeks; as a result, little is known about how a long-term HFSD influences the metabolic profile of these mice. Therefore, the aim of this investigation was to examine the effects of consuming a HFSD for 42 weeks on the development of hyperinsulinaemia and glucose intolerance in male C57Bl/6 mice. Two cohorts of HFSD mice were studied at independent institutes and they underwent an oral glucose tolerance test (OGTT) with measures of plasma insulin and free fatty acids (FFA). Age-matched chow-fed control mice were also studied. The HFSD-fed mice were hyperinsulinaemic and grossly obese, being over 25 g heavier than chow-fed mice, which was due to a marked expansion of subcutaneous adipose tissue. This was associated with a 3-fold increase in liver lipid content. Glucose tolerance, however, was either the same or better than control mice due to the preservation of glucose disposal as revealed by a dynamic stable isotope-labelled OGTT. In addition, plasma FFAs were suppressed to lower levels in HFSD mice during the OGTT. In conclusion, we have made the paradoxical observation that long-term HFSD feeding results in the resolution of glucose intolerance in the C57Bl/6 mouse. Mechanistically, we propose that the gross expansion of subcutaneous adipose tissue increases the glucose disposal capacity of the HFSD-fed mouse, which overcomes the prevailing insulin resistance to improve glucose tolerance.

scholarly journals Notch1 Haploinsufficiency in Mice Accelerates Adipogenesis

2021 ◽  
Author(s):  
Kazutoshi Yamaguchi ◽  
Motoharu Hayashi ◽  
Yasuhiro Uchida ◽  
Xian Cheng ◽  
Takayuki Nakayama ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Notch Signaling ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Proliferation Markers ◽  
Fat Accumulation ◽  
Over Expression ◽  
Insulin Tolerance

Abstract Notch signaling has been recognized recently as a key regulator of metabolism. Here, we determined the role of Notch1 in adipogenesis in wild-type (WT) and Notch1 hetero-mutant (N1+/-) mice provided with 12-week normal or high-fat diet. Haploinsufficiency of Notch1 was associated with adipose tissue accumulation despite similar food intake. White adipose tissue (WAT) of N1+/- showed accumulation of adipogenic cells (CD34 + CD68 + cells), crown-like structures, and upregulation of cell proliferation markers (cyclin D1 and Ki67). Notch1 expression in WAT reached peak levels in 8-week-old WT mice in parallel with fat accumulation, especially under HF/HS-feeding, whereas such increment was blunted in N1+/- mice. Downstream of Notch1 haploinsufficiency, over-expression of adipogenic factors PPARγ and C/EBPα was noted following down-regulation of downstream transcriptional factors of Notch signaling (Hes-1, Pref-1, and Sox9). Both pharmacological Notch signal inhibition and Notch1 knockdown enhanced adipogenesis of 3T3-L1 preadipocytes. N1+/- mice showed impaired glucose and insulin tolerance with downregulation of IRS-1 and GLUT4 in WAT after high-fat diet. Taken together, our results suggest that haploinsufficiency of Notch1 promotes fat accumulation and adipogenesis and provides a mechanistic link between Notch signaling and development of metabolic syndrome.

scholarly journals Notch1 haploinsufficiency in mice accelerates adipogenesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazutoshi Yamaguchi ◽  
Motoharu Hayashi ◽  
Yasuhiro Uchida ◽  
Xian Wu Cheng ◽  
Takayuki Nakayama ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Notch Signaling ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Proliferation Markers ◽  
Fat Accumulation ◽  
Over Expression ◽  
Insulin Tolerance

AbstractNotch signaling has been recognized recently as a key regulator of metabolism. Here, we determined the role of Notch1 in adipogenesis in wild-type (WT) and Notch1 hetero-mutant (N1+/−) mice provided with 12-week normal or high-fat diet. Haploinsufficiency of Notch1 was associated with adipose tissue accumulation despite similar food intake. White adipose tissue (WAT) of N1+/− showed accumulation of adipogenic cells (CD34+CD68+ cells), crown-like structures, and upregulation of cell proliferation markers (cyclin D1 and Ki67). Notch1 expression in WAT reached peak levels in 8-week-old WT mice in parallel with fat accumulation, especially under HF/HS-feeding, whereas such increment was blunted in N1+/− mice. Downstream of Notch1 haploinsufficiency, over-expression of adipogenic factors PPARγ and C/EBPα was noted following down-regulation of downstream transcriptional factors of Notch signaling (Hes-1, Pref-1, and Sox9). Both pharmacological Notch signal inhibition and Notch1 knockdown enhanced adipogenesis of 3T3-L1 preadipocytes. N1+/− mice showed impaired glucose and insulin tolerance with downregulation of IRS-1 and GLUT4 in WAT after high-fat diet. Taken together, our results suggest that haploinsufficiency of Notch1 promotes fat accumulation and adipogenesis and provides a mechanistic link between Notch signaling and development of metabolic syndrome.

scholarly journals Distinct Effects of a High Fat Diet on Bone in Skeletally Mature and Developing Male C57BL/6J Mice

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1666
Author(s):  
Dean S. Ross ◽  
Tzu-Hsuan Yeh ◽  
Shalinie King ◽  
Julia Mathers ◽  
Mark S. Rybchyn ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Bone Formation ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Age Groups ◽  
Oral Glucose ◽  
Rna Expression ◽  
High Fat ◽  
Mineral Density ◽  
Skeletal Fragility

Increased risks of skeletal fractures are common in patients with impaired glucose handling and type 2 diabetes mellitus (T2DM). The pathogenesis of skeletal fragility in these patients remains ill-defined as patients present with normal to high bone mineral density. With increasing cases of glucose intolerance and T2DM it is imperative that we develop an accurate rodent model for further investigation. We hypothesized that a high fat diet (60%) administered to developing male C57BL/6J mice that had not reached skeletal maturity would over represent bone microarchitectural implications, and that skeletally mature mice would better represent adult-onset glucose intolerance and the pre-diabetes phenotype. Two groups of developing (8 week) and mature (12 week) male C57BL/6J mice were placed onto either a normal chow (NC) or high fat diet (HFD) for 10 weeks. Oral glucose tolerance tests were performed throughout the study period. Long bones were excised and analysed for ex vivo biomechanical testing, micro-computed tomography, 2D histomorphometry and gene/protein expression analyses. The HFD increased fasting blood glucose and significantly reduced glucose tolerance in both age groups by week 7 of the diets. The HFD reduced biomechanical strength, both cortical and trabecular indices in the developing mice, but only affected cortical outcomes in the mature mice. Similar results were reflected in the 2D histomorphometry. Tibial gene expression revealed decreased bone formation in the HFD mice of both age groups, i.e., decreased osteocalcin expression and increased sclerostin RNA expression. In the mature mice only, while the HFD led to a non-significant reduction in runt-related transcription factor 2 (Runx2) RNA expression, this decrease became significant at the protein level in the femora. Our mature HFD mouse model more accurately represents late-onset impaired glucose tolerance/pre-T2DM cases in humans and can be used to uncover potential insights into reduced bone formation as a mechanism of skeletal fragility in these patients.

scholarly journals Partial Deficiency of Zfp217 Resists High-Fat Diet-Induced Obesity by Increasing Energy Metabolism in Mice

2021 ◽  
Vol 22 (10) ◽  
pp. 5390
Author(s):  
Qianhui Zeng ◽  
Nannan Wang ◽  
Yaru Zhang ◽  
Yuxuan Yang ◽  
Shuangshuang Li ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Energy Metabolism ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Glycolipid Metabolism ◽  
Partial Deficiency

Obesity-induced adipose tissue dysfunction and disorders of glycolipid metabolism have become a worldwide research priority. Zfp217 plays a crucial role in adipogenesis of 3T3-L1 preadipocytes, but about its functions in animal models are not yet clear. To explore the role of Zfp217 in high-fat diet (HFD)-induced obese mice, global Zfp217 heterozygous knockout (Zfp217+/−) mice were constructed. Zfp217+/− mice and Zfp217+/+ mice fed a normal chow diet (NC) did not differ significantly in weight gain, percent body fat mass, glucose tolerance, or insulin sensitivity. When challenged with HFD, Zfp217+/− mice had less weight gain than Zfp217+/+ mice. Histological observations revealed that Zfp217+/− mice fed a high-fat diet had much smaller white adipocytes in inguinal white adipose tissue (iWAT). Zfp217+/− mice had improved metabolic profiles, including improved glucose tolerance, enhanced insulin sensitivity, and increased energy expenditure compared to the Zfp217+/+ mice under HFD. We found that adipogenesis-related genes were increased and metabolic thermogenesis-related genes were decreased in the iWAT of HFD-fed Zfp217+/+ mice compared to Zfp217+/− mice. In addition, adipogenesis was markedly reduced in mouse embryonic fibroblasts (MEFs) from Zfp217-deleted mice. Together, these data indicate that Zfp217 is a regulator of energy metabolism and it is likely to provide novel insight into treatment for obesity.

Long-term High Fat Diet Consumption Reversibly Alters Feeding Behavior via a Dopamine-Associated Mechanism in Mice

2021 ◽  
pp. 113470
Author(s):  
Everett Altherr ◽  
Aundrea Rainwater ◽  
Darian Kaviani ◽  
Qijun Tang ◽  
Ali D. Güler
Keyword(s):  
Feeding Behavior ◽  
High Fat Diet ◽  
High Fat

scholarly journals Carbonyl Reductase 1 Overexpression in Adipose Amplifies Local Glucocorticoid Action and Impairs Glucose Tolerance in Lean Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A806-A806
Author(s):  
Rachel Bell ◽  
Elisa Villalobos ◽  
Mark Nixon ◽  
Allende Miguelez-Crespo ◽  
Matthew Sharp ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Fat Mass ◽  
High Fat Diet ◽  
Fasting Glucose ◽  
High Fat ◽  
Male And Female ◽  
Over Expression ◽  
Female Mice ◽  
Diet Induced Obesity

Abstract Glucocorticoids play a critical role in metabolic homeostasis. Chronic or excessive activation of the glucocorticoid receptor (GR) in adipose tissue contributes to metabolic disorders such as glucose intolerance and insulin resistance. Steroid-metabolising enzymes in adipose, such as 11β-HSD1 or 5α-reductase, modulate the activation of GR by converting primary glucocorticoids into more or less potent ligands. Carbonyl reductase 1 (CBR1) is a novel regulator of glucocorticoid metabolism, converting corticosterone/cortisol to 20β-dihydrocorticosterone/cortisol (20β-DHB/F); a metabolite which retains GR activity. CBR1 is abundant in adipose tissue and increased in obese adipose of mice and humans1 and increased Cbr1 expression is associated with increased fasting glucose1. We hypothesised that increased Cbr1/20β-DHB in obese adipose contributes to excessive GR activation and worsens glucose tolerance. We generated a novel murine model of adipose-specific Cbr1 over-expression (R26-Cbr1Adpq) by crossing conditional knock-in mice with Adiponectin-Cre mice. CBR1 protein and activity were doubled in subcutaneous adipose tissue of male and female R26-Cbr1Adpq mice compared with floxed controls; corresponding to a two-fold increase 20β-DHB (1.6 vs. 4.2ng/g adipose; P=0.0003; n=5-7/group). There were no differences in plasma 20β-DHB or corticosterone. Bodyweight, lean or fat mass, did not differ between male or female R26-Cbr1Adpq mice and floxed controls. Lean male R26-Cbr1Adpq mice had higher fasting glucose (9.5±0.3 vs. 8.4±0.3mmol/L; P=0.04) and worsened glucose tolerance (AUC 1819±66 vs. 1392±14; P=0.03). Female R26-Cbr1Adpq mice also had a worsened glucose tolerance but fasting glucose was not altered with genotype. There were no differences in fasting insulin or non-esterified fatty acid between genotypes in either sex. Expression of GR-induced genes Pnpla2, Gilz and Per1, were increased in adipose of R26-Cbr1Adpq mice. Following high-fat diet induced obesity, no differences in bodyweight, lean or fat mass, with genotype were observed in male and female mice, and genotype differences in fasting glucose and glucose tolerance were abolished. In conclusion, adipose-specific over-expression of Cbr1 in lean male and female mice led to increased levels of 20β-DHB in adipose but not plasma, and both sexes having worsened glucose tolerance. The influence of adipose CBR1/20β-DHB on glucose tolerance was not associated with altered fat mass or bodyweight and was attenuated by high-fat diet-induced obesity. These metabolic consequences of Cbr1 manipulation require careful consideration given the wide variation in CBR1 expression in the human population, the presence of inhibitors and enhancers in many foodstuffs and the proposed use of inhibitors as an adjunct for cancer treatment regimens. Reference: Morgan et al., Scientific Reports. 2017; 7.

α1-Antitrypsin A treatment attenuates neutrophil elastase accumulation and enhances insulin sensitivity in adipose tissue of mice fed a high-fat diet.

2021 ◽  
Author(s):  
Randall F. D'Souza ◽  
Stewart W.C. Masson ◽  
Jonathan S. T. Woodhead ◽  
Samuel L James ◽  
Caitlin MacRae ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Neutrophil Elastase ◽  
High Fat Diet ◽  
Tolerance Test ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Insulin Tolerance

Neutrophils accumulate in insulin sensitive tissues during obesity and may play a role in impairing insulin sensitivity. The major serine protease expressed by neutrophils is neutrophil elastase (NE), which is inhibited endogenously by α1-antitrypsin A (A1AT). We investigated the effect of exogenous (A1AT) treatment on diet induced metabolic dysfunction. Male C57Bl/6j mice fed a chow or a high fat diet (HFD) were randomized to receive 3x weekly i.p injections of either Prolastin (human A1AT; 2mg) or vehicle (PBS) for 10 weeks. Prolastin treatment did not affect plasma NE concentration, body weight, glucose tolerance or insulin sensitivity in chow fed mice. In contrast, Prolastin treatment attenuated HFD induced increases in plasma and white adipose tissue (WAT) NE without affecting circulatory neutrophil levels or increases in body weight. Prolastin-treated mice fed a HFD had improved insulin sensitivity, as assessed by insulin tolerance test, and this was associated with higher insulin-dependent IRS-1 (insulin receptor substrate) and AktSer473phosphorylation, and reduced inflammation markers in WAT but not liver or muscle. In 3T3-L1 adipocytes, Prolastin reversed recombinant NE-induced impairment of insulin-stimulated glucose uptake and IRS-1 phosphorylation. Furthermore, PDGF mediated p-AktSer473 activation and glucose uptake (which is independent of IRS-1) was not affected by recombinant NE treatment. Collectively, our findings suggest that NE infiltration of WAT during metabolic overload contributes to insulin-resistance by impairing insulin-induced IRS-1 signaling.

scholarly journals Patchouli Alcohol from Pogostemon Cablin Prevents Development of Obesity and Improves Glucose Tolerance in High Fat Diet-induced Obese Mice (P06-107-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jihye Lee ◽  
Seong-Ho Lee
Keyword(s):  
Body Weight ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Oral Glucose ◽  
Male Mice ◽  
Fat Pad ◽  
High Fat ◽  
Patchouli Alcohol ◽  
Brown Adipose ◽  
Pogostemon Cablin

Abstract Objectives Patchouli alcohol is a sesquiterpene alcohol found in Pogostemon cablin. Recently, we observed that patchouli alcohol reduced lipid accumulation in differentiated 3T3-L1 adipocytes and increased glucose uptake in differentiated C2C12 myocytes. This study was designed to investigate anti-obese and anti-diabetic activities of patchouli alcohol using high fat diet-induced obese mouse model. Methods Forty-eight 5-week old C57BL/6 J male mice were assigned into four groups and fed with 1) normal diet (control), 2) high fat diet, 3) high fat diet with gavaging 25 mg of patchouli alcohol/kg body weight and 4) high fat diet with gavaging 50 mg of patchouli alcohol/kg body weight. High fat diet or control diets were provided to each treatment group for four weeks and then different doses of patchouli alcohol (0, 25 or 50 mg/kg body weight) was orally administered for following 8 weeks with the diet. At age of week 17, all animals were sacrificed, fat tissues were collected, and tissue weight was measured. In addition, twenty C57BL/6 J male mice were assigned into the same treatment groups above. At the end of the 8 weeks (age of week 17), the mice were fasted for 12 h and the oral glucose tolerance test was performed after intraperitoneal injection of 2 g of anhydrous glucose/kg body weight. The blood was collected from tail at 0, 15, 30, 90 and 120 min after injection and blood glucose level was analyzed using glucose meter. Results Treatment of patchouli alcohol (50 mg/kg body weight) significantly reduced body weight and accumulation of body fat pads which was highly induced by feeding of high fat diet. An analysis of individual fat pad weights (expressed as mg weight of fat pad/g body weight) revealed a significant decrease of epididymal and retroperitoneal fat pad in patchouli alcohol-treated mice whereas brown adipose tissue were not significantly altered. And, slightly improved glucose tolerance was observed at 90 and 120 minutes after glucose injection in mice treated with patchouli alcohol (50 mg/kg body weight) compared to those fed with high fat diet alone. Conclusions We propose a potential use of patchouli alcohol as an anti-obesity compound in obese population. Funding Sources NIFA Hatch grant. Supporting Tables, Images and/or Graphs

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