Transplantation of adipose tissue lacking PAI-1 improves glucose tolerance and attenuates cardiac metabolic abnormalities in high-fat 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.

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PAI-1 Exacerbates White Adipose Tissue Dysfunction and Metabolic Dysregulation in High Fat Diet-Induced Obesity

Frontiers in Pharmacology ◽

10.3389/fphar.2018.01087 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 11

Author(s):

Lin Wang ◽

Liyuan Chen ◽

Zheran Liu ◽

Yaofang Liu ◽

Mao Luo ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

High Fat Diet ◽

High Fat ◽

Diet Induced Obesity ◽

Metabolic Dysregulation ◽

Adipose Tissue Dysfunction ◽

Pai 1

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Inhibitory Effects of Fermented Ougan (Citrus reticulata cv. Suavissima) Juice on High-Fat Diet-induced Obesity Associated with White Adipose Tissue Browning and Gut Microbiota Modulation in Mice

Food & Function ◽

10.1039/d0fo03423a ◽

2021 ◽

Author(s):

Xiao Guo ◽

Xuedan Cao ◽

Xiugui Fang ◽

Ailing Guo ◽

Erhu Li

Keyword(s):

Adipose Tissue ◽

Lactic Acid ◽

Lactic Acid Bacteria ◽

Gut Microbiota ◽

High Fat Diet ◽

Citrus Reticulata ◽

Inhibitory Effects ◽

High Fat ◽

Diet Induced Obesity ◽

Tissue Browning

In this study, Ougan juice (OJ) and lactic acid bacteria fermented Ougan juice (FOJ) were investigated individually for their capability of preventing obesity in high-fat diet (HFD)-fed C57BL/6J mice. After...

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Trans-palmitoleic Acid Reduces Adiposity via Increased Lipolysis in a Rodent Model of Diet-Induced Obesity

British Journal Of Nutrition ◽

10.1017/s0007114521001501 ◽

2021 ◽

pp. 1-24

Author(s):

L. Irasema Chávaro-Ortiz ◽

Brenda D. Tapia-Vargas ◽

Mariel Rico-Hidalgo ◽

Ruth Gutiérrez-Aguilar ◽

María E. Frigolet

Keyword(s):

Adipose Tissue ◽

Lipid Metabolism ◽

Visceral Adipose Tissue ◽

High Fat Diet ◽

Palmitoleic Acid ◽

Rodent Model ◽

Adipocyte Size ◽

High Fat ◽

Diet Induced Obesity ◽

Visceral Adipose

Abstract Obesity is defined as increased adiposity, which leads to metabolic disease. The growth of adipose tissue depends on its capacity to expand, through hyperplasia or hypertrophy, in order to buffer energy surplus. Also, during the establishment of obesity, adipose tissue expansion reflects adipose lipid metabolism (lipogenesis and/or lipolysis). It is well known that dietary factors can modify lipid metabolism promoting or preventing the development of metabolic abnormalities that concur with obesity. Trans-palmitoleic acid (TP), a biomarker of dairy consumption, has been associated with reduced adiposity in clinical studies. Thus, we aimed to evaluate the effect of TP over adiposity and lipid metabolism-related genes in a rodent model of diet-induced obesity (DIO). To fulfil this aim, we fed C57BL/6 mice with a Control or a High Fat diet, added with or without TP (3g/kg diet), during 11 weeks. Body weight and food intake were monitored, fat pads were weighted, histology of visceral adipose tissue was analysed, and lipid metabolism-related gene expression was explored by qPCR. Results show that TP consumption prevented weight gain induced by high fat diet, reduced visceral adipose tissue weight, and adipocyte size, while increasing the expression of lipolytic molecules. In conclusion, we show for the first time that TP influences adipose tissue metabolism, specifically lipolysis, resulting in decreased adiposity and reduced adipocyte size in a DIO mice model.

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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.

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Myricanol modulates skeletal muscle–adipose tissue crosstalk to alleviate high‐fat diet‐induced obesity and insulin resistance

British Journal of Pharmacology ◽

10.1111/bph.14802 ◽

2019 ◽

Vol 176 (20) ◽

pp. 3983-4001 ◽

Cited By ~ 8

Author(s):

Shengnan Shen ◽

Qiwen Liao ◽

Tian Zhang ◽

Ruile Pan ◽

Ligen Lin

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Adipose Tissue ◽

High Fat Diet ◽

High Fat ◽

Diet Induced Obesity

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Tissue-specific expression of Sprouty1 in mice protects against high-fat diet-induced fat accumulation, bone loss and metabolic dysfunction

British Journal Of Nutrition ◽

10.1017/s0007114511006209 ◽

2011 ◽

Vol 108 (6) ◽

pp. 1025-1033 ◽

Cited By ~ 7

Author(s):

Sumithra Urs ◽

Terry Henderson ◽

Phuong Le ◽

Clifford J. Rosen ◽

Lucy Liaw

Keyword(s):

Adipose Tissue ◽

Bone Loss ◽

Bone Mass ◽

Body Fat ◽

High Fat Diet ◽

Conditional Knockout ◽

Whole Body ◽

High Fat ◽

Tissue Specific ◽

Diet Induced Obesity

We recently characterised Sprouty1 (Spry1), a growth factor signalling inhibitor as a regulator of marrow progenitor cells promoting osteoblast differentiation at the expense of adipocytes. Adipose tissue-specific Spry1 expression in mice resulted in increased bone mass and reduced body fat, while conditional knockout of Spry1 had the opposite effect with decreased bone mass and increased body fat. Because Spry1 suppresses normal fat development, we tested the hypothesis that Spry1 expression prevents high-fat diet-induced obesity, bone loss and associated lipid abnormalities, and demonstrate that Spry1 has a long-term protective effect on mice fed a high-energy diet. We studied diet-induced obesity in mice with fatty acid binding promoter-driven expression or conditional knockout of Spry1 in adipocytes. Phenotyping was performed by whole-body dual-energy X-ray absorptiometry, microCT, histology and blood analysis. In conditional Spry1-null mice, a high-fat diet increased body fat by 40 %, impaired glucose regulation and led to liver steatosis. However, overexpression of Spry1 led to 35 % (P < 0·05) lower body fat, reduced bone loss and normal metabolic function compared with single transgenics. This protective phenotype was associated with decreased circulating insulin (70 %) and leptin (54 %; P < 0·005) compared with controls on a high-fat diet. Additionally, Spry1 expression decreased adipose tissue inflammation by 45 %. We show that conditional Spry1 expression in adipose tissue protects against high-fat diet-induced obesity and associated bone loss.

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