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

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.

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Increased Plasma Dipeptidyl Peptidase IV (DPP IV) Activity and Decreased DPP IV Activity of Visceral But Not Subcutaneous Adipose Tissue in Impaired Glucose Tolerance Rats Induced by High-Fat or High-Sucrose Diet

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.32.463 ◽

2009 ◽

Vol 32 (3) ◽

pp. 463-467 ◽

Cited By ~ 18

Author(s):

Yasushi Kirino ◽

Takayuki Kamimoto ◽

Youichi Sato ◽

Kazuyoshi Kawazoe ◽

Kazuo Minakuchi ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Tolerance ◽

Impaired Glucose Tolerance ◽

Subcutaneous Adipose Tissue ◽

High Fat ◽

Dpp Iv ◽

Sucrose Diet ◽

High Sucrose Diet ◽

Subcutaneous Adipose ◽

High Sucrose

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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 ◽

10.3390/molecules26196006 ◽

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.

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The effects of myo-inositol and probiotic supplementation in a high-fat-fed preclinical model of glucose intolerance in pregnancy

British Journal Of Nutrition ◽

10.1017/s0007114519003039 ◽

2019 ◽

Vol 123 (5) ◽

pp. 516-528 ◽

Cited By ~ 1

Author(s):

J. F. Plows ◽

J. M. Ramos Nieves ◽

F. Budin ◽

K. Mace ◽

C. M. Reynolds ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Tolerance ◽

Glucose Intolerance ◽

Lactobacillus Rhamnosus ◽

Tissue Expression ◽

Tolerance Test ◽

Preclinical Model ◽

Oral Glucose ◽

High Fat ◽

The Impact

AbstractGlucose intolerance during pregnancy – a major driver of gestational diabetes mellitus (GDM) – has significant short- and long-term health consequences for both the mother and child. As GDM prevalence continues to escalate, there is growing need for preventative strategies. There is limited but suggestive evidence that myo-inositol (MI) and probiotics (PB) could improve glucose tolerance during pregnancy. The present study tested the hypothesis that MI and/or PB supplementation would reduce the risk of glucose intolerance during pregnancy. Female C57BL/6 mice were randomised to receive either no treatment, MI, PB (Lactobacillus rhamnosus and Bifidobacterium lactis) or both (MIPB) for 5 weeks. They were then provided with a high-fat diet for 1 week before mating commenced and throughout mating/gestation, while remaining on their respective treatments. An oral glucose tolerance test occurred at gestational day (GD) 16·5 and tissue collection at GD 18·5. Neither MI nor PB, separately or combined, improved glucose tolerance. However, MI and PB both independently increased adipose tissue expression of Ir, Irs1, Akt2 and Pck1, and PB also increased Pparγ. MI was associated with reduced gestational weight gain, whilst PB was associated with increased maternal fasting glucose, total cholesterol and pancreas weight. These results suggest that MI and PB may improve insulin intracellular signalling in adipose tissue but this did not translate to meaningful differences in glucose tolerance. The absence of fasting hyperglycaemia or insulin resistance suggests this is a very mild model of GDM, which may have affected our ability to assess the impact of these nutrients.

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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

10.1101/2021.07.25.453688 ◽

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.

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

Nutrients ◽

10.3390/nu13051666 ◽

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.

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