Microbial Reconstitution Reverses Early Female Puberty Induced by Maternal High-fat Diet During Lactation

Abstract Recent work shows that gut microbial dysbiosis contributes to the risk of obesity in children whose mothers consume a high-fat diet (HFD) during both gestation and lactation or during gestation alone. Obesity predisposes children to developing precocious puberty. However, to date, no study has examined how maternal HFD (MHFD) during lactation regulates the gut microbiota (GM), pubertal timing, and fertility of offspring. Here, we found that MHFD during lactation markedly altered the GM of offspring. The pups developed juvenile obesity, early puberty, irregular estrous cycles, and signs of disrupted glucose metabolism. Remarkably, permitting coprophagia between MHFD and maternal normal chow offspring successfully reversed the GM changes as well as early puberty and insulin insensitivity. Our data suggest that microbial reconstitution may prevent or treat early puberty associated with insulin resistance.

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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.

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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.

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Melatonin Improves Glucose Homeostasis and Endothelial Vascular Function in High-Fat Diet-Fed Insulin-Resistant Mice

Endocrinology ◽

10.1210/en.2009-0425 ◽

2009 ◽

Vol 150 (12) ◽

pp. 5311-5317 ◽

Cited By ~ 90

Author(s):

Claudio Sartori ◽

Pierre Dessen ◽

Caroline Mathieu ◽

Anita Monney ◽

Jonathan Bloch ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Signal Transduction ◽

Glucose Tolerance ◽

Glucose Homeostasis ◽

High Fat Diet ◽

High Fat ◽

Insulin Resistant ◽

Normal Chow ◽

Underlying Mechanisms

Abstract Obesity and insulin resistance represent a problem of utmost clinical significance worldwide. Insulin-resistant states are characterized by the inability of insulin to induce proper signal transduction leading to defective glucose uptake in skeletal muscle tissue and impaired insulin-induced vasodilation. In various pathophysiological models, melatonin interacts with crucial molecules of the insulin signaling pathway, but its effects on glucose homeostasis are not known. In a diet-induced mouse model of insulin resistance and normal chow-fed control mice, we sought to assess the effects of an 8-wk oral treatment with melatonin on insulin and glucose tolerance and to understand underlying mechanisms. In high-fat diet-fed mice, but not in normal chow-fed control mice, melatonin significantly improved insulin sensitivity and glucose tolerance, as evidenced by a higher rate of glucose infusion to maintain euglycemia during hyperinsulinemic clamp studies and an attenuated hyperglycemic response to an ip glucose challenge. Regarding underlying mechanisms, we found that melatonin restored insulin-induced vasodilation to skeletal muscle, a major site of glucose utilization. This was due, at least in part, to the improvement of insulin signal transduction in the vasculature, as evidenced by increased insulin-induced phosphorylation of Akt and endoethelial nitric oxide synthase in aortas harvested from melatonin-treated high-fat diet-fed mice. In contrast, melatonin had no effect on the ability of insulin to promote glucose uptake in skeletal muscle tissue in vitro. These data demonstrate for the first time that in a diet-induced rodent model of insulin resistance, melatonin improves glucose homeostasis by restoring the vascular action of insulin.

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Cytochrome P-450 CYP2E1 knockout mice are protected against high-fat diet-induced obesity and insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00258.2011 ◽

2012 ◽

Vol 302 (5) ◽

pp. E532-E539 ◽

Cited By ~ 50

Author(s):

Haihong Zong ◽

Michal Armoni ◽

Chava Harel ◽

Eddy Karnieli ◽

Jeffrey E. Pessin

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Knockout Mice ◽

High Fat Diet ◽

Whole Body ◽

High Fat ◽

Normal Chow ◽

Glucose Output ◽

Fat Diets

Conventional (whole body) CYP2E1 knockout mice displayed protection against high-fat diet-induced weight gain, obesity, and hyperlipidemia with increased energy expenditure despite normal food intake and spontaneous locomotor activity. In addition, the CYP2E1 knockout mice displayed a marked improvement in glucose tolerance on both normal chow and high-fat diets. Euglycemic-hyperinsulinemic clamps demonstrated a marked protection against high-fat diet-induced insulin resistance in CYP2E1 knockout mice, with enhanced adipose tissue glucose uptake and insulin suppression of hepatic glucose output. In parallel, adipose tissue was protected against high-fat diet-induced proinflammatory cytokine production. Taken together, these data demonstrate that the CYP2E1 deletion protects mice against high-fat diet-induced insulin resistance with improved glucose homeostasis in vivo.

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Metabolic dysfunction in female mice with disruption of 5α-reductase 1

Journal of Endocrinology ◽

10.1530/joe-16-0125 ◽

2017 ◽

Vol 232 (1) ◽

pp. 29-36 ◽

Cited By ~ 10

Author(s):

Dawn E W Livingstone ◽

Emma M Di Rollo ◽

Tracy C-S Mak ◽

Karen Sooy ◽

Brian R Walker ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

Stress Responses ◽

High Fat Diet ◽

Metabolic Dysfunction ◽

Male Mice ◽

High Fat ◽

Female Mice ◽

Normal Chow ◽

Transcript Profiles

5α-Reductases irreversibly catalyse A-ring reduction of pregnene steroids, including glucocorticoids and androgens. Genetic disruption of 5α-reductase 1 in male mice impairs glucocorticoid clearance and predisposes to glucose intolerance and hepatic steatosis upon metabolic challenge. However, it is unclear whether this is driven by changes in androgen and/or glucocorticoid action. Female mice with transgenic disruption of 5α-reductase 1 (5αR1-KO) were studied, representing a ‘low androgen’ state. Glucocorticoid clearance and stress responses were studied in mice aged 6 months. Metabolism was assessed in mice on normal chow (aged 6 and 12 m) and also in a separate cohort following 1-month high-fat diet (aged 3 m). Female 5αR1-KO mice had adrenal suppression (44% lower AUC corticosterone after stress), and upon corticosterone infusion, accumulated hepatic glucocorticoids (~27% increased corticosterone). Female 5αR1-KO mice aged 6 m fed normal chow demonstrated insulin resistance (~35% increased area under curve (AUC) for insulin upon glucose tolerance testing) and hepatic steatosis (~33% increased hepatic triglycerides) compared with controls. This progressed to obesity (~12% increased body weight) and sustained insulin resistance (~38% increased AUC insulin) by age 12 m. Hepatic transcript profiles supported impaired lipid β-oxidation and increased triglyceride storage. Female 5αR1-KO mice were also predisposed to develop high-fat diet-induced insulin resistance. Exaggerated predisposition to metabolic disorders in female mice, compared with that seen in male mice, after disruption of 5αR1 suggests phenotypic changes may be underpinned by altered metabolism of glucocorticoids rather than androgens.

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The Immunomodulating Effect of Baicalin on Inflammation and Insulin Resistance in High-Fat-Diet-Induced Obese Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/5531367 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Ji-Won Noh ◽

Oh-Jun Kwon ◽

Byung-Cheol Lee

Keyword(s):

Insulin Resistance ◽

Immune Cells ◽

High Fat Diet ◽

Metabolic Diseases ◽

Liver Weight ◽

Tolerance Test ◽

The Body ◽

High Fat ◽

Normal Chow ◽

Anti Inflammatory

Background. Obesity is a chronic low-grade systemic inflammation state, which causes insulin resistance, diabetes, and other metabolic diseases. Baicalin is known to have anti-inflammatory and antiobesity effects. In this study, we investigated the cellular and molecular immunological effects of baicalin on obesity-induced inflammation. Methods. Male C57BL/6 mice were assigned to four groups: the normal chow, high-fat diet (HFD), BC2 (HFD + baicalin 200 mg/kg), and BC4 (HFD + baicalin 400 mg/kg) group; the three groups except normal chow were fed with a high-fat diet for 8 weeks to induce obesity followed by baicalin treatment with two doses for 8 weeks. The body weight, epididymal fat weight, liver weight, food intake, oral glucose tolerance test (OGTT), oral fat tolerance test (OFTT), and serum lipids were measured. We evaluated insulin resistance by measuring the serum insulin level and homeostatic model assessment of insulin resistance (HOMA-IR). Also, the major obesity-associated immune cells including monocytes, macrophages, T lymphocytes, and dendritic cells in the blood, fat, and liver and the inflammatory and insulin signaling-related gene expressions in the fat and liver were evaluated. Results. Baicalin significantly reduced the body weight and liver weight and improved serum fasting glucose, insulin, HOMA-IR, free fatty acid, HDL cholesterol, and the levels of glucose and triglyceride at each time point in the OGTT and OFTT. In the analysis of immune cells, baicalin significantly decreased inflammatory Ly6Chi monocytes, M1 adipose tissue macrophages (ATMs), and M1 Kupffer cells. On the contrary, baicalin increased anti-inflammatory M2 ATMs and liver CD4+ T cells and CD4/CD8 ratio. In the analysis of inflammatory and insulin signaling molecules, baicalin significantly downregulated the gene expression of tumor necrosis factor-α, F4/80, and C-C motif chemokine 2 while upregulated the insulin receptor mRNA expression. Conclusion. From these results, baicalin can be a promising treatment option for obesity and its related metabolic diseases based on its anti-inflammatory property.

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Maternal High-Fat Diet During Pre-Conception and Gestation Predisposes Adult Female Offspring to Metabolic Dysfunction in Mice

Frontiers in Endocrinology ◽

10.3389/fendo.2021.780300 ◽

2022 ◽

Vol 12 ◽

Author(s):

Brian Akhaphong ◽

Brigid Gregg ◽

Doga Kumusoglu ◽

Seokwon Jo ◽

Kanakadurga Singer ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Beta Cell ◽

Adult Female ◽

High Fat Diet ◽

Female Offspring ◽

Cell Fraction ◽

Adult Offspring ◽

High Fat ◽

Normal Chow

The risk of obesity in adulthood is subject to programming in the womb. Maternal obesity contributes to programming of obesity and metabolic disease risk in the adult offspring. With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of maternal high-fat diet (HFD) during pregnancy on offspring’s metabolic heath trajectory. In the present study, we determined the long-term metabolic outcomes on adult male and female offspring of dams fed with HFD during pregnancy. C57BL/6J dams were fed either Ctrl or 60% Kcal HFD for 4 weeks before and throughout pregnancy, and we tested glucose homeostasis in the adult offspring. Both Ctrl and HFD-dams displayed increased weight during pregnancy, but HFD-dams gained more weight than Ctrl-dams. Litter size and offspring birthweight were not different between HFD-dams or Ctrl-dams. A significant reduction in random blood glucose was evident in newborns from HFD-dams compared to Ctrl-dams. Islet morphology and alpha-cell fraction were normal but a reduction in beta-cell fraction was observed in newborns from HFD-dams compared to Ctrl-dams. During adulthood, male offspring of HFD-dams displayed comparable glucose tolerance under normal chow. Male offspring re-challenged with HFD displayed glucose intolerance transiently. Adult female offspring of HFD-dams demonstrated normal glucose tolerance but displayed increased insulin resistance relative to controls under normal chow diet. Moreover, adult female offspring of HFD-dams displayed increased insulin secretion in response to high-glucose treatment, but beta-cell mass were comparable between groups. Together, these data show that maternal HFD at pre-conception and during gestation predisposes the female offspring to insulin resistance in adulthood.

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