Dataset Information

Obesogenic and diabetic effects of CD44 in mice are sexually dimorphic and dependent on genetic background.

ABSTRACT:

Introduction

CD44 is a candidate gene for obesity and diabetes development and may be a critical mediator of a systemic inflammation associated with obesity and diabetes.

Methods

We investigated the relationship of CD44 with obesity in CD44-deficient mice challenged with a high-fat diet.

Results

In mice fed a diet high in fat, cholesterol, and sucrose for 12 weeks fat mass accumulation was reduced in CD44-deficient mice bred onto both a C57BL/6J and the naturally TLR deficient C3H/HeJ background. Reduced fat mass could not be attributed to lower food intake or an increase in energy expenditure as measured by indirect calorimetry. However, we observed a 40-60% lower mRNA expression of the inflammation markers, F4/80, CD11b, TNF-α, and CD14, in adipose tissue of CD44-deficient mice on the C57BL/6J background but not the C3H/HeJ background, perhaps indicating that alternative factors may be affecting adiposity in this model. Measures of hepatic steatosis and insulin sensitivity were improved in CD44-deficient mice on a C57BL/6J but not in the C3H/HeJ mice. These results were highly sexually dimorphic as there were no detectable effects of CD44 inactivation in female mice on a C57BL/6 J or C3H/HeJ background.

Conclusion

CD44 was associated with adiposity, liver fat, and glucose in male mice. However, the effects of CD44 on obesity may be independent of TLR4 signaling.

SUBMITTER: VerHague M

PROVIDER: S-EPMC8996418 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Obesogenic and diabetic effects of CD44 in mice are sexually dimorphic and dependent on genetic background.

VerHague Melissa M Albright Jody J Barron Keri K Kim Myungsuk M Bennett Brian J BJ

Biology of sex differences 20220411 1

<h4>Introduction</h4>CD44 is a candidate gene for obesity and diabetes development and may be a critical mediator of a systemic inflammation associated with obesity and diabetes.<h4>Methods</h4>We investigated the relationship of CD44 with obesity in CD44-deficient mice challenged with a high-fat diet.<h4>Results</h4>In mice fed a diet high in fat, cholesterol, and sucrose for 12 weeks fat mass accumulation was reduced in CD44-deficient mice bred onto both a C57BL/6J and the naturally TLR defici ...[more]

PMID: 35410390

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Project description:BackgroundWomen have a higher risk of developing osteoarthritis (OA) than men, including with obesity. To better understand this disparity, we investigated sex differences in metabolic and inflammatory factors associated with OA using a diet-induced mouse model of obesity. We hypothesized that 20 weeks of high-fat diet (HFD) would induce sexually dimorphic changes in both systemic and local risk factors of knee OA.MethodsMale and female C57BL/6J mice were fed Chow or HFD from 6 to 26 weeks of age (n = 12 per diet and sex). We performed broad metabolic phenotyping, 16 S gut microbiome analysis, targeted gene expression analysis of synovium-infrapatellar fat tissue, targeted gene expression and proteomic analysis of articular cartilage, chondrocyte metabolic profiling, and OA histopathology. Two-way ANOVA statistics were utilized to determine the contribution of sex and diet and their interaction on outcomes.ResultsMice fed HFD weighed 1.76-fold (p < 0.0001) and 1.60-fold (p < 0.0001) more than male and female Chow cohorts, respectively, with both sexes reaching similar body fat levels (male: 43.9 ± 2.2%; female: 44.1 ± 3.8%). HFD caused greater cartilage pathology (p < 0.024) and synovial hyperplasia (p < 0.038) versus Chow in both sexes. Cartilage pathology was greater in male versus female mice (p = 0.048), and only male mice developed osteophytes with HFD (p = 0.044). Both sexes exhibited metabolic inflexibility on HFD, but only male mice developed glucose intolerance (p < 0.0001), fatty liver (p < 0.0001), and elevated serum amylase (p < 0.0001) with HFD versus Chow. HFD treatment caused sex-dependent differences in gut microbiota beta diversity (p = 0.01) and alteration in specific microbiome clades, such as a HFD-dependent reduction in abundance of Bifidobacterium only in male mice. In knee synovium and infrapatellar fat tissue, HFD upregulated the expression of pro-inflammatory and pro-fibrotic genes predominantly in female mice. In cartilage, lipid metabolism proteins were more abundant with HFD in male mice, whereas proteins involved in glycolysis/gluconeogenesis and biosynthesis of amino acids were greater in cartilage of female mice. Sex-dependent metabolic differences were observed in cartilage from young, healthy mice prior to pubertal maturation, but not in primary juvenile chondrocytes studied in vitro.ConclusionsHFD induced numerous sex differences in metabolic and inflammatory outcomes, especially in joint tissues, suggesting that sex-specific cellular processes are involved during development of early-stage OA with obesity.

Project description:IntroductionReducing Optic Atrophy 1 (OPA1) expression in skeletal muscle in male mice induces Activation Transcription Factor 4 (ATF4) and the integrated stress response (ISR). Additionally, skeletal muscle secretion of Fibroblast Growth Factor 21 (FGF21) is increased, which mediates metabolic adaptations including resistance to diet-induced obesity (DIO) and glucose intolerance in these mice. Although FGF21 induction in this model can be reversed with pharmacological attenuation of ER stress, it remains to be determined if ATF4 is responsible for FGF21 induction and its metabolic benefits in this model.MethodsWe generated mice with homozygous floxed Opa1 and Atf4 alleles and a tamoxifen-inducible Cre transgene controlled by the human skeletal actin promoter to enable simultaneous depletion of OPA1 and ATF4 in skeletal muscle (mAO DKO). Mice were fed high fat (HFD) or control diet and evaluated for ISR activation, body mass, fat mass, glucose tolerance, insulin tolerance and circulating concentrations of FGF21 and growth differentiation factor 15 (GDF15).ResultsIn mAO DKO mice, ATF4 induction is absent. Other indices of ISR activation, including XBP1s, ATF6, and CHOP were induced in mAO DKO males, but not in mOPA1 or mAO DKO females. Resistance to diet-induced obesity was not reversed in mAO DKO mice of both sexes. Circulating FGF21 and GDF15 illustrated sexually dimorphic patterns. Loss of OPA1 in skeletal muscle increases circulating FGF21 in mOPA1 males, but not in mOPA1 females. Additional loss of ATF4 decreased circulating FGF21 in mAO DKO male mice, but increased circulating FGF21 in female mAO DKO mice. Conversely, circulating GDF15 was increased in mAO DKO males and mOPA1 females, but not in mAO DKO females.ConclusionSex differences exist in the transcriptional outputs of the ISR following OPA deletion in skeletal muscle. Deletion of ATF4 in male and female OPA1 KO mice does not reverse the resistance to DIO. Induction of circulating FGF21 is ATF4 dependent in males, whereas induction of circulating GDF15 is ATF4 dependent in females. Elevated GDF15 in males and FGF21 in females could reflect activation by other transcriptional outputs of the ISR, that maintain mitokine-dependent metabolic protection in an ATF4-independent manner.

Dataset Information

Obesogenic and diabetic effects of CD44 in mice are sexually dimorphic and dependent on genetic background.

Introduction

Methods

Results

Conclusion

Publications

Obesogenic and diabetic effects of CD44 in mice are sexually dimorphic and dependent on genetic background.

Similar Datasets

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