Stress Aggravates High-Fat-Diet-Induced Insulin Resistance via a Mechanism That Involves the Amygdala and Is Associated with Changes in Neuroplasticity

2018 ◽  
Vol 107 (2) ◽  
pp. 147-157 ◽  
Author(s):  
Sheng-Feng Tsai ◽  
Hung-Tsung Wu ◽  
Pei-Chun Chen ◽  
Yun-Wen Chen ◽  
Megan Yu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Tissue Expansion ◽  
Plasma Corticosterone ◽  
High Fat ◽  
Obesity In Mice ◽  
Bilateral Lesions

Background: The notion that exposure to chronic stress predisposes individuals to developing type 2 diabetes (T2D) has gained much attention in recent decades. Long-term stress induces neuroadaptation in the amygdala and increases corticosterone levels. Corticosterone, the major stress hormone in rodents, induces insulin resistance and obesity in mice. However, little is known about whether the stress-induced amygdalar neuroadaptation could promote the risk of T2D. Methods: We used an 11-week high-fat diet (HFD) feeding paradigm to induce insulin dysfunction in mice, followed by implementation of a 10-day social defeat (SD) stress protocol. Results: Mice receiving SD at the beginning of the HFD feeding aggravated HFD-induced insulin resistance and white adipose tissue expansion. HFD mice had higher levels of plasma corticosterone, which was not affected by the SD. The SD stress upregulated the expression of TrkB and synaptotagmin-4 in the amygdala of HFD mice. Bilateral lesions of the central amygdalae before SD stress inhibited the stress-induced aggravating effect without affecting the HFD-induced elevation of plasma corticosterone. Conclusions: Stress aggravates HFD-induced insulin resistance and neuroadaptation in the amygdala. The HFD-induced insulin resistance is amygdala-dependent. Understanding the role of stress-induced amygdalar adaptation in the development of T2D could inform therapies aimed at reducing chronic stressors to decrease the risk for T2D.

scholarly journals Role of Muscle c-Jun NH2-Terminal Kinase 1 in Obesity-Induced Insulin Resistance

2009 ◽  
Vol 30 (1) ◽  
pp. 106-115 ◽  
Author(s):  
Guadalupe Sabio ◽  
Norman J. Kennedy ◽  
Julie Cavanagh-Kyros ◽  
Dae Young Jung ◽  
Hwi Jin Ko ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Akt Activation ◽  
Peripheral Insulin Resistance ◽  
Diet Induced Obesity

ABSTRACT Obesity caused by feeding of a high-fat diet (HFD) is associated with an increased activation of c-Jun NH2-terminal kinase 1 (JNK1). Activated JNK1 is implicated in the mechanism of obesity-induced insulin resistance and the development of metabolic syndrome and type 2 diabetes. Significantly, Jnk1 − / − mice are protected against HFD-induced obesity and insulin resistance. Here we show that an ablation of the Jnk1 gene in skeletal muscle does not influence HFD-induced obesity. However, muscle-specific JNK1-deficient (MKO) mice exhibit improved insulin sensitivity compared with control wild-type (MWT) mice. Thus, insulin-stimulated AKT activation is suppressed in muscle, liver, and adipose tissue of HFD-fed MWT mice but is suppressed only in the liver and adipose tissue of MKO mice. These data demonstrate that JNK1 in muscle contributes to peripheral insulin resistance in response to diet-induced obesity.

scholarly journals RGC32 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice

2014 ◽  
Vol 224 (2) ◽  
pp. 127-137 ◽  
Author(s):  
Xiao-Bing Cui ◽  
Jun-Na Luan ◽  
Jianping Ye ◽  
Shi-You Chen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Tolerance Test ◽  
High Fat ◽  
Diet Induced Obesity

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases and many other chronic diseases. Adipose tissue inflammation is a critical link between obesity and insulin resistance and type 2 diabetes and a contributor to disease susceptibility and progression. The objective of this study was to determine the role of response gene to complement 32 (RGC32) in the development of obesity and insulin resistance. WT and RGC32 knockout (Rgc32−/− (Rgcc)) mice were fed normal chow or high-fat diet (HFD) for 12 weeks. Metabolic, biochemical, and histologic analyses were performed. 3T3-L1 preadipocytes were used to study the role of RGC32 in adipocytes in vitro. Rgc32−/− mice fed with HFD exhibited a lean phenotype with reduced epididymal fat weight compared with WT controls. Blood biochemical analysis and insulin tolerance test showed that RGC32 deficiency improved HFD-induced dyslipidemia and insulin resistance. Although it had no effect on adipocyte differentiation, RGC32 deficiency ameliorated adipose tissue and systemic inflammation. Moreover, Rgc32−/− induced browning of adipose tissues and increased energy expenditure. Our data indicated that RGC32 plays an important role in diet-induced obesity and insulin resistance, and thus it may serve as a potential novel drug target for developing therapeutics to treat obesity and metabolic disorders.

Altered bone metabolism after high fat diet and exercise: role of Wnt signaling and insulin resistance

2016 ◽  
Author(s):  
Ann-Kristin Picke ◽  
Lykke Sylow ◽  
Lisbeth L V Moller ◽  
Rasmus Kjobsted ◽  
Erik Richter ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Wnt Signaling ◽  
Bone Metabolism ◽  
High Fat Diet ◽  
High Fat ◽  
Diet And Exercise

scholarly journals A Newly Developed Synbiotic Yogurt Prevents Diabetes by Improving the Microbiome–Intestine–Pancreas Axis

2021 ◽  
Vol 22 (4) ◽  
pp. 1647
Author(s):  
Brandi Miller ◽  
Rabina Mainali ◽  
Ravinder Nagpal ◽  
Hariom Yadav
Keyword(s):  
High Fat Diet ◽  
Microbiota Composition ◽  
Preventive Strategies ◽  
Human Origin ◽  
High Fat ◽  
Diabetes In Mice ◽  
Diabetes Progression ◽  
Gut Microbiota Composition

The prevalence of type 2 diabetes mellitus (T2D) is increasing worldwide, and there are no long-term preventive strategies to stop this growth. Emerging research shows that perturbations in the gut microbiome significantly contribute to the development of T2D, while microbiome modulators may be beneficial for T2D prevention. However, microbiome modulators that are effective, safe, affordable, and able to be administered daily are not yet available. Based on our previous pro- and prebiotic studies, we developed a novel synbiotic yogurt comprised of human-origin probiotics and plant-based prebiotics and investigated its impact on diet- and streptozotocin-induced T2D in mice. We compared the effects of our synbiotic yogurt to those of a commercially available yogurt (control yogurt). Interestingly, we found that the feeding of the synbiotic yogurt significantly reduced the development of hyperglycemia (diabetes) in response to high-fat diet feeding and streptozotocin compared to milk-fed controls. Surprisingly, the control yogurt exacerbated diabetes progression. Synbiotic yogurt beneficially modulated the gut microbiota composition compared to milk, while the control yogurt negatively modulated it by significantly increasing the abundance of detrimental bacteria such as Proteobacteria and Enterobacteriaceae. In addition, the synbiotic yogurt protected pancreatic islet morphology compared to the milk control, while the control yogurt demonstrated worse effects on islets. These results suggest that our newly developed synbiotic yogurt protects against diabetes in mice and can be used as a therapeutic to prevent diabetes progression.

Abstract 015: Increased 20-HETE Levels Contribute to Impaired Glucose Metabolism and Type 2 Diabetes in Cyp4a14 Knockout Mice Fed on High Fat Diet.

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Varunkumar G Pandey ◽  
Lars Bellner ◽  
Victor Garcia ◽  
Joseph Schragenheim ◽  
Andrew Cohen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Weight Gain ◽  
Blood Glucose ◽  
High Fat Diet ◽  
Plasma Insulin ◽  
High Fat ◽  
Plasma Insulin Levels

20-HETE (20-Hydroxyeicosatetraenoic acid) is a cytochrome P450 ω-hydroxylase metabolite of arachidonic acid that promotes endothelial dysfunction, microvascular remodeling and hypertension. Previous studies have shown that urinary 20-HETE levels correlate with BMI and plasma insulin levels. However, there is no direct evidence for the role of 20-HETE in the regulation of glucose metabolism, obesity and type 2 diabetes mellitus. In this study we examined the effect of 20-SOLA (2,5,8,11,14,17-hexaoxanonadecan-19-yl-20-hydroxyeicosa-6(Z),15(Z)-dienoate), a water-soluble 20-HETE antagonist, on blood pressure, weight gain and blood glucose in Cyp4a14 knockout (Cyp4a14-/-) mice fed high-fat diet (HFD). The Cyp4a14-/- male mice exhibit high vascular 20-HETE levels and display 20-HETE-dependent hypertension. There was no difference in weight gain and fasting blood glucose between Cyp4a14-/- and wild type (WT) on regular chow. When subjected to HFD for 15 weeks, a significant increase in weight was observed in Cyp4a14-/- as compared to WT mice (56.5±3.45 vs. 30.2±0.7g, p<0.05). Administration of 20-SOLA (10mg/kg/day in drinking water) significantly attenuated the weight gain (28.7±1.47g, p<0.05) and normalized blood pressure in Cyp4a14-/- mice on HFD (116±0.3 vs. 172.7±4.6mmHg, p<0.05). HFD fed Cyp4a14-/- mice exhibited hyperglycemia as opposed to normal glucose levels in WT on a HFD (154±1.9 vs. 96.3±3.0 mg/dL, p<0.05). 20-SOLA prevented the HFD-induced hyperglycemia in Cyp4a14-/- mice (91±8mg/dL, p<0.05). Plasma insulin levels were markedly high in Cyp4a14-/- mice vs. WT on HFD (2.66±0.7 vs. 0.58±0.18ng/mL, p<0.05); corrected by the treatment with 20-SOLA (0.69±0.09 ng/mL, p<0.05). Importantly, glucose and insulin tolerance tests showed impaired glucose homeostasis and insulin resistance in Cyp4a14-/- mice on HFD; ameliorated by treatment with 20-SOLA. This novel finding that blockade of 20-HETE actions by 20-SOLA prevents HFD-induced obesity and restores glucose homeostasis in Cyp4a14-/- mice suggests that 20-HETE contributes to obesity, hyperglycemia and insulin resistance in HFD induced metabolic disorder. The molecular mechanisms underlying 20-HETE mediated metabolic dysfunction are being currently explored.

scholarly journals Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

2020 ◽  
Vol 295 (31) ◽  
pp. 10842-10856 ◽  
Author(s):  
Wen Liu ◽  
Ye Yin ◽  
Meijing Wang ◽  
Ting Fan ◽  
Yuyu Zhu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Low Grade ◽  
High Fat ◽  
Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

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

2019 ◽  
Vol 317 (6) ◽  
pp. E973-E983 ◽  
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.

scholarly journals Nrf2 Represses FGF21 During Long-Term High-Fat Diet-Induced Obesity in Mice

Diabetes ◽  
2011 ◽  
Vol 60 (10) ◽  
pp. 2465-2473 ◽  
Author(s):  
D. V. Chartoumpekis ◽  
P. G. Ziros ◽  
A. I. Psyrogiannis ◽  
A. G. Papavassiliou ◽  
V. E. Kyriazopoulou ◽  
...  
Keyword(s):  
High Fat Diet ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Obesity In Mice
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