Chronic high fat feeding and prolonged fasting in liver-specific ANGPTL4 knockout mice

Obesity is associated with dyslipidemia, ectopic lipid deposition and insulin resistance. In mice, the global or adipose-specific loss of function of the protein angiopoietin-like 4 (ANGPTL4) leads to decreased plasma triglyceride levels, enhanced adipose triglyceride uptake, and protection from high-fat diet-induced glucose intolerance. ANGPTL4 is also expressed highly in the liver, but the role of liver-derived ANGPTL4 is unclear. The goal of this study was to determine the contribution of hepatocyte ANGPTL4 to triglyceride and glucose homeostasis in mice during a high fat diet challenge. We generated hepatocyte-specific ANGPTL4 deficient (Angptl4LivKO) mice, fed them a 60% kCal/fat diet (HFD) for 6 months, and assessed triglyceride, liver, and glucose metabolic phenotypes. We also explored the effects of prolonged fasting on Angptl4LivKO mice. The loss of hepatocyte-derived Angptl4 led to no major changes in triglyceride partitioning or lipoprotein lipase activity compared to control mice. Interestingly, although there was no difference in fasting plasma triglyceride levels after a 6 h fast, after an 18 h fast normal chow diet fed Angptl4LivKO mice had lower triglyceride levels than control mice. On a HFD, Angptl4LivKO mice initially showed no difference in glucose tolerance and insulin sensitivity, but improved glucose tolerance emerged in these mice after 6 months on HFD. Our data suggest that hepatocyte ANGPTL4 does not directly regulate triglyceride partitioning, but that loss of liver-derived ANGPTL4 may be protective from HFD-induced glucose intolerance and influence plasma TG metabolism during prolonged fasting.

Download Full-text

Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice

Endocrinology ◽

10.1210/en.2008-0971 ◽

2009 ◽

Vol 150 (5) ◽

pp. 2109-2117 ◽

Cited By ~ 244

Author(s):

Elodie Riant ◽

Aurélie Waget ◽

Haude Cogo ◽

Jean-François Arnal ◽

Rémy Burcelin ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Intolerance ◽

High Fat Diet ◽

Chow Diet ◽

High Fat ◽

Normal Chow ◽

Visceral Adipose ◽

Deficient Mice ◽

Normal Chow Diet

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERα-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-α) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERα-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

Download Full-text

Dietary sodium chloride attenuates increased β-cell mass to cause glucose intolerance in mice under a high-fat diet

PLoS ONE ◽

10.1371/journal.pone.0248065 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0248065

Author(s):

Keigo Taki ◽

Hiroshi Takagi ◽

Tomonori Hirose ◽

Runan Sun ◽

Hiroshi Yaginuma ◽

...

Keyword(s):

Glucose Tolerance ◽

Glucose Intolerance ◽

Plasma Glucose ◽

High Fat Diet ◽

Cell Mass ◽

Tolerance Test ◽

Chow Diet ◽

High Fat ◽

Lower Plasma ◽

Β Cell

Excessive sodium salt (NaCl) or fat intake is associated with a variety of increased health risks. However, whether excessive NaCl intake accompanied by a high-fat diet (HFD) affects glucose metabolism has not been elucidated. In this study, C57BL/6J male mice were fed a normal chow diet (NCD), a NCD plus high-NaCl diet (NCD plus NaCl), a HFD, or a HFD plus high-NaCl diet (HFD plus NaCl) for 30 weeks. No significant differences in body weight gain, insulin sensitivity, and glucose tolerance were observed between NCD-fed and NCD plus NaCl-fed mice. In contrast, body and liver weights were decreased, but the weight of epididymal white adipose tissue was increased in HFD plus NaCl-fed compared to HFD-fed mice. HFD plus NaCl-fed mice had lower plasma glucose levels in an insulin tolerance test, and showed higher plasma glucose and lower plasma insulin levels in an intraperitoneal glucose tolerance test compared to HFD-fed mice. The β-cell area and number of islets were decreased in HFD plus NaCl-fed compared to HFD-fed mice. Increased Ki67-positive β-cells, and increased expression levels of Ki67, CyclinB1, and CyclinD1 mRNA in islets were observed in HFD-fed but not HFD plus NaCl-fed mice when compared to NCD-fed mice. Our data suggest that excessive NaCl intake accompanied by a HFD exacerbates glucose intolerance, with impairment in insulin secretion caused by the attenuation of expansion of β-cell mass in the pancreas.

Download Full-text

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.

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms22105390 ◽

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.

Download Full-text

CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high-fat-fed C57BL/6 mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00215.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. E973-E983 ◽

Cited By ~ 3

Author(s):

Annie Hasib ◽

Chandani K. Hennayake ◽

Deanna P. Bracy ◽

Aimée R. Bugler-Lamb ◽

Louise Lantier ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

High Fat Diet ◽

Critical Role ◽

Chow Diet ◽

Wild Type ◽

High Fat ◽

Insulin Resistant ◽

Beneficial Effects

Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient ( cd44−/−) mice and wild-type littermates ( cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44−/− mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44−/− mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44−/− mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44−/− compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44−/− mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44−/− mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.

Download Full-text

Effect of A Polyphenol-Rich Canarium album Extract on the Composition of the Gut Microbiota of Mice Fed a High-Fat Diet

Molecules ◽

10.3390/molecules23092188 ◽

2018 ◽

Vol 23 (9) ◽

pp. 2188 ◽

Cited By ~ 5

Author(s):

Ning-Ning Zhang ◽

Wen-Hui Guo ◽

Han Hu ◽

A-Rong Zhou ◽

Qing-Pei Liu ◽

...

Keyword(s):

Gut Microbiota ◽

High Fat Diet ◽

High Throughput Sequencing ◽

Chow Diet ◽

Microbiota Composition ◽

High Fat ◽

Canarium Album ◽

Normal Chow ◽

Gut Microbiota Composition ◽

Medium Dose

This study investigated the influence of Canarium album extract (CAext) on intestinal microbiota composition of mice fed a high-fat diet (HFD). Kun Ming (KM) mice were fed either a normal chow diet or a HFD for six weeks. At the seventh week, HFD-fed mice were gavaged daily with saline, or a different dose of CAext for four weeks, respectively. Then, the composition of the gut microbiota was analyzed by high-throughput sequencing technology. Analysis of fecal microbial populations, grouped by phyla, showed significant increases of Firmicutes and Verrucomicrobia, but a decrease of Bacteroidetes in all CAext-fed mice. Particularly, CAext gavage in a low dose or a medium dose caused a significant increase in the proportion of Akkermansia. These findings suggested that CAext can alter the gut microbiota composition of HFD-fed mice, and had a potential prebiotic effects on Akkermansia.

Download Full-text

Effect of stevia on the gut microbiota and glucose tolerance in a murine model of diet-induced obesity

FEMS Microbiology Ecology ◽

10.1093/femsec/fiaa079 ◽

2020 ◽

Vol 96 (6) ◽

Cited By ~ 2

Author(s):

Sarah L Becker ◽

Edna Chiang ◽

Anna Plantinga ◽

Hannah V Carey ◽

Garret Suen ◽

...

Keyword(s):

Glucose Tolerance ◽

Gut Microbiota ◽

Glucose Intolerance ◽

High Fat Diet ◽

High Fat ◽

Low Fat ◽

Treatment Groups ◽

Low Fat Diet ◽

Taxonomic Groups ◽

Induced Changes

ABSTRACT Artificial sweeteners have been shown to induce glucose intolerance by altering the gut microbiota; however, little is known about the effect of stevia. Here, we investigate whether stevia supplementation induces glucose intolerance by altering the gut microbiota in mice, hypothesizing that stevia would correct high fat diet-induced glucose intolerance and alter the gut microbiota. Mice were split into four treatment groups: low fat, high fat, high fat + saccharin and high fat + stevia. After 10 weeks of treatment, mice consuming a high fat diet (60% kcal from fat) developed glucose intolerance and gained more weight than mice consuming a low fat diet. Stevia supplementation did not impact body weight or glucose intolerance. Differences in species richness and relative abundances of several phyla were observed in low fat groups compared to high fat, stevia and saccharin. We identified two operational taxonomic groups that contributed to differences in beta-diversity between the stevia and saccharin groups: Lactococcus and Akkermansia in females and Lactococcus in males. Our results demonstrate that stevia does not rescue high fat diet-induced changes in glucose tolerance or the microbiota, and that stevia results in similar alterations to the gut microbiota as saccharin when administered in concordance with a high fat diet.

Download Full-text

Commensal Bacteria Impact a Protozoan’s Integration into the Murine Gut Microbiota in a Dietary Nutrient-Dependent Manner

Applied and Environmental Microbiology ◽

10.1128/aem.00303-20 ◽

2020 ◽

Vol 86 (11) ◽

Author(s):

Yanxia Wei ◽

Jing Gao ◽

Yanbo Kou ◽

Liyuan Meng ◽

Xingping Zheng ◽

...

Keyword(s):

Microbial Community ◽

High Fat Diet ◽

Commensal Bacteria ◽

Intestinal Microbiome ◽

Chow Diet ◽

Dependent Manner ◽

High Fat ◽

Normal Chow ◽

Dietary Nutrient ◽

Potential Factors

ABSTRACT Our current understanding of the host-microbiota interaction in the gut is dominated by studies focused primarily on prokaryotic bacterial communities. However, there is an underappreciated symbiotic eukaryotic protistic community that is an integral part of mammalian microbiota. How commensal protozoan bacteria might interact to form a stable microbial community remains poorly understood. Here, we describe a murine protistic commensal, phylogenetically assigned as Tritrichomonas musculis, whose colonization in the gut resulted in a reduction of gut bacterial abundance and diversity in wild-type C57BL/6 mice. Meanwhile, dietary nutrient and commensal bacteria also influenced the protozoan’s intestinal colonization and stability. While mice fed a normal chow diet had abundant T. musculis organisms, switching to a Western-type high-fat diet led to the diminishment of the protozoan from the gut. Supplementation of inulin as a dietary fiber to the high-fat diet partially restored the protozoan’s colonization. In addition, a cocktail of broad-spectrum antibiotics rendered permissive engraftment of T. musculis even under a high-fat, low-fiber diet. Furthermore, oral administration of Bifidobacterium spp. together with dietary supplementation of inulin in the high-fat diet impacted the protozoan’s intestinal engraftment in a bifidobacterial species-dependent manner. Overall, our study described an example of dietary-nutrient-dependent murine commensal protozoan-bacterium cross talk as an important modulator of the host intestinal microbiome. IMPORTANCE Like commensal bacteria, commensal protozoa are an integral part of the vertebrate intestinal microbiome. How protozoa integrate into a commensal bacterium-enriched ecosystem remains poorly studied. Here, using the murine commensal Tritrichomonas musculis as a proof of concept, we studied potential factors involved in shaping the intestinal protozoal-bacterial community. Understanding the rules by which microbes form a multispecies community is crucial to prevent or correct microbial community dysfunctions in order to promote the host’s health or to treat diseases.

Download Full-text

ADAR1 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00175.2020 ◽

2020 ◽

Author(s):

Xiaobing Cui ◽

Jia Fei ◽

Sisi Chen ◽

Gaylen L. Edwards ◽

Shi-You Chen

Keyword(s):

Insulin Resistance ◽

Food Intake ◽

High Fat Diet ◽

Peptide Yy ◽

Tolerance Test ◽

Chow Diet ◽

High Fat ◽

Blood Biochemical ◽

Insulin Tolerance ◽

Normal Chow

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases, and many other chronic diseases. The objective of this study was to determine the role of adenosine deaminase acting on RNA 1 (ADAR1) in the development of obesity and insulin resistance. Wild-type (WT) and heterozygous ADAR1-deficient (Adar1+/-) mice were fed normal chow or high-fat diet (HFD) for 12 weeks. Adar1+/- mice fed with HFD exhibited a lean phenotype with reduced fat mass compared with WT controls, although no difference was found under chow diet conditions. Blood biochemical analysis and insulin tolerance test showed that Adar1+/- improved HFD-induced dyslipidemia and insulin resistance. Metabolic studies showed that food intake was decreased in Adar1+/- mice compared with the WT mice under HFD conditions. Paired feeding studies further demonstrated that Adar1+/- protected mice from HFD-induced obesity through decreased food intake. Furthermore, Adar1+/- restored the increased ghrelin expression in stomach and the decreased serum peptide YY levels under HFD conditions. These data indicate that ADAR1 may contribute to diet-induce obesity, at least partially, through modulating the ghrelin and peptide YY expression and secretion.

Download Full-text

NOX4 Deficiency Exacerbates the Impairment of Cystatin C-Dependent Hippocampal Neurogenesis by a Chronic High Fat Diet

Genes ◽

10.3390/genes11050567 ◽

2020 ◽

Vol 11 (5) ◽

pp. 567

Author(s):

Piyanart Jiranugrom ◽

Ik Dong Yoo ◽

Min Woo Park ◽

Ji Hwan Ryu ◽

Jong-Seok Moon ◽

...

Keyword(s):

Cystatin C ◽

High Fat Diet ◽

Metabolic Stress ◽

Hippocampal Neurogenesis ◽

High Fat ◽

Nadph Oxidase 4 ◽

Normal Physiological Condition ◽

Normal Chow ◽

Differentiation Marker

Hippocampal neurogenesis is linked with a cognitive process under a normal physiological condition including learning, memory, pattern separation, and cognitive flexibility. Hippocampal neurogenesis is altered by multiple factors such as the systemic metabolic changes. NADPH oxidase 4 (NOX4) has been implicated in the regulation of brain function. While the role of NOX4 plays in the brain, the mechanism by which NOX4 regulates hippocampal neurogenesis under metabolic stress is unclear. In this case, we show that NOX4 deficiency exacerbates the impairment of hippocampal neurogenesis by inhibiting neuronal maturation by a chronic high fat diet (HFD). NOX4 deficiency resulted in less hippocampal neurogenesis by decreasing doublecortin (DCX)-positive neuroblasts, a neuronal differentiation marker, and their branched-dendrites. Notably, NOX4 deficiency exacerbates the impairment of hippocampal neurogenesis by chronic HFD. Moreover, NOX4 deficiency had a significant reduction of Cystatin C levels, which is critical for hippocampal neurogenesis, under chronic HFD as well as normal chow (NC) diet. Furthermore, the reduction of Cystatin C levels was correlated with the impairment of hippocampal neurogenesis in NOX4 deficient and wild-type (WT) mice under chronic HFD. Our results suggest that NOX4 regulates the impairment of Cystatin C-dependent hippocampal neurogenesis under chronic HFD.

Download Full-text