Thrombin-mediated proteoglycan synthesis utilizes both protein-tyrosine kinase and serine/threonine kinase receptor transactivation in vascular smooth muscle cells

Background: GPCR transactivation of PTKRs and TGF-αRs mediates proteoglycan synthesis in human VSMC. Results: Transactivation of TGF-αRs is integrin-dependent, and inhibition of both transactivation pathways blocks proteoglycan synthesis. Conclusion: GPCR utilize transactivation pathways and not classical signaling in proteoglycan synthesis. Significance: GPCR transactivation of receptor kinase pathways may be broader and more significant than previously recognized

Role of IL-6 in Exercise Training- and Cold-Induced UCP1 Expression in Subcutaneous White Adipose Tissue

Expression of brown adipose tissue (BAT) associated proteins like uncoupling protein 1 (UCP1) in inguinal WAT (iWAT) has been suggested to alter iWAT metabolism. The aim of this study was to investigate the role of interleukin-6 (IL-6) in exercise training and cold exposure-induced iWAT UCP1 expression. The effect of daily intraperitoneal injections of IL-6 (3 ng/g) in C57BL/6 mice for 7 days on iWAT UCP1 expression was examined. In addition, the expression of UCP1 in iWAT was determined in response to 3 days of cold exposure (4°C) and 5 weeks of exercise training in wild type (WT) and whole body IL-6 knockout (KO) mice. Repeated injections of IL-6 in C57BL/6 mice increased UCP1 mRNA but not UCP1 protein content in iWAT. Cold exposure increased iWAT UCP1 mRNA content similarly in IL-6 KO and WT mice, while exercise training increased iWAT UCP1 mRNA in WT mice but not in IL-6 KO mice. Additionally, a cold exposure-induced increase in iWAT UCP1 protein content was blunted in IL-6 KO mice, while UCP1 protein content in iWAT was lower in both untrained and exercise trained IL-6 KO mice than in WT mice. In conclusion, repeated daily increases in plasma IL-6 can increase iWAT UCP1 mRNA content and IL-6 is required for an exercise training-induced increase in iWAT UCP1 mRNA content. In addition IL-6 is required for a full induction of UCP1 protein expression in response to cold exposure and influences the UCP1 protein content iWAT of both untrained and exercise trained animals

Differential response to resistance training in CHF according to ACE genotype

The Angiotensin Converting Enzyme (ACE) gene may influence the risk of heart disease and the response to various forms of exercise training may be at least partly dependent on the ACE genotype. We aimed to determine the effect of ACE genotype on the response to moderate intensity circuit resistance training in chronic heart failure (CHF) patients. Methods: The relationship between ACE genotype and the response to 11 weeks of resistance exercise training was determined in 37 CHF patients (New York Heart Association Functional Class=2.3±0.5; left ventricular ejection fraction 28±7%; age 64±12 years; 32:5 male:female) who were randomised to either resistance exercise (n=19) or inactive control group (n=18). Outcome measures included V˙ O2peak, peak power output and muscle strength and endurance. ACE genotype was determined using standard methods. Results: At baseline, patients who were homozygous for the I allele had higher V˙ O2peak (p=0.02) and peak power (p=0.003) compared to patients who were homozygous for the D allele. Patients with the D allele, who were randomised to resistance training, compared to non-exercising controls, had greater peak power increases (ID pb0.001; DD pb0.001) when compared with patients homozygous for the I allele, who did not improve. No significant genotype-dependent changes were observed in V˙ O2peak, muscle strength, muscle endurance or lactate threshold. Conclusion: ACE genotype may have a role in exercise tolerance in CHF and could also influence the effectiveness of resistance training in this condition

Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling

Objective: Interleukin (IL)-18 plays a crucial role in maintaining metabolic homeostasis and levels of this cytokine are influenced by gender, age, and sex hormones. The role of gender on IL-18 signaling, however, is unclear. We hypothesized that the presence of female sex hormone could preserve the metabolic phenotype of the IL-18R−/− animals. Methods: We studied female mice with a global deletion of the α isoform of the IL-18 receptor (IL-18R−/−) and littermates control. Three studies were done: 1) animals fed a high fat diet (HFD) for 16 weeks; 2) animals fed chow diet for 72 weeks and 3) animals (3 weeks-old) randomized to either bilateral ovariectomy (OVX) or control surgery (SHAM) and followed for 16 weeks. Results: Female IL-18R−/− mice gained less weight and maintained glucose homeostasis on a chow diet compared with HFD, but no differences between genotypes were observed. The maintenance of body weight and glucose homeostasis in IL-18R−/− mice was lost with aging. By 72 weeks of age, IL-18R−/− mice became heavier compared with WT mice due to an increase in both visceral and subcutaneous adiposity and displayed glucose intolerance. OVX did not affect body weight in IL-18R−/− mice but exacerbated glucose intolerance and impaired liver insulin signaling when compared with SHAM mice. Conclusions: Female mice harboring a global deletion of the IL-18R, only present the same phenotype as reported in male IL-18R−/− mice if they are aged or have undergone OVX, in which circulating estrogen is likely to be blunted. The role of estrogen signaling in the protection against altered metabolic homeostasis in IL-18R−/− mice appears to be mediated by liver insulin signaling. We therefore suggest that the metabolic effects mediated by loss of IL-18 signaling are only present in a female sex hormone free environment. Keywords: IL-18, Obesity, Insulin resistance, Gende

ERα Governs the Sexual Dimorphism in HSP72-mediated Control of Mitochondrial Function, Exercise Capacity, and Insulin Sensitivity in Mice

HSP72 is a chaperone protein upregulated during exercise. Levels are reduced in aging and obesity, and increased levels are correlated with improvements in metabolic health in male mice and humans. Male HSP72KO mice have increased body fat, decreased insulin sensitivity, and a loss of mitochondrial quality control. Specifically, male KO mice have increased cytosolic Parkin levels, but the protein is unable to move to the mitochondria resulting in enlarged, hyperfused mitochondria associated with metabolic dysfunction. PURPOSE: To investigate the role of HSP72 in female mice to better understand the sexual dimorphism involved in the heat shock response. METHODS: HSP72KO and WT male and female mice were analzyed for insulin sensitivity, expercise capacity, gene and protein expression, and mitochondrial morphology and respiratory capacity. RESULTS: Overall, female HSP72KO mice showed the opposite of male KO mice. Female KOs had reduced body weight (p\u3c0.0001) and gonadal fat (p=0.005), improved insulin sensitivity (p=0.0179), and increased voluntary wheel running compared to WT controls and male mice (p=0.0079). Cytosolic Parkin was increased, but maintained its ability to translocate to the mitochondria. Hence, skeletal muscle mitochondria were smaller and more spherical in the KO mice, indicative of increased fission signaling. Respirometry analysis showed enhanced complex I, II, and IV activity in the mitochondria of skeletal muscle (p=0.0127, 0.003, & 0.0009). The improved insulin sensitivity, exercise capacity, and mitochondrial fission in female KO mice mimics the phenotype of estrogen receptor a (ERa) overexpression mice, and female HSP72 KO mice showed increased levels of ERa and its encoding gene, while the male KO mice did not. CONCLUSION: Given the fact that KO males are negatively affected by the loss of HSP72 and do not show an increase in ERa, this sexual dimorphism appears underpinned by a compensatory upregulation of the estrogen receptor alpha (ERa). The beneficial, and potentially therapeutic, role of HSP72, as well as the consequences associated with reduced levels of the protein, has been repeatedly demonstrated in male mice and humans. These data indicate that HSP72 plays a unique role in the regulation of metabolic and mitochondrial health in females

Chaperoning to the metabolic party:the emerging therapeutic role of heat-shock proteins in obesity and type 2 diabetes

Background: From their initial, accidental discovery 50 years ago, the highly conserved Heat Shock Proteins (HSPs) continue to exhibit fundamental roles in the protection of cell integrity. Meanwhile, in the midst of an obesity epidemic, research demonstrates a key involvement of low grade inflammation, and mitochondrial dysfunction amongst other mechanisms, in the pathology of insulin resistance and type 2 diabetes mellitus (T2DM). In particular, tumor necrosis factor alpha (TNFα), endoplasmic reticulum (ER) and oxidative stress all appear to be associated with obesity and stimulate inflammatory kinases such as c jun amino terminal kinase (JNK), inhibitor of NF-κβ kinase (IKK) and protein kinase C (PKC) which in turn, inhibit insulin signaling. Mitochondrial dysfunction in skeletal muscle has also been proposed to be prominent in the pathogenesis of T2DM either by reducing the ability to oxidize fatty acids, leading to the accumulation of deleterious lipid species in peripheral tissues such as skeletal muscle and liver, or by altering the cellular redox state. Since HSPs act as molecular chaperones and demonstrate crucial protective functions in stressed cells, we and others have postulated that the manipulation of HSP expression in metabolically relevant tissues represents a therapeutic avenue for obesity-induced insulin resistance. Scope of Review: This review summarizes the literature from both animal and human studies, that has examined how HSPs, particularly the inducible HSP, Heat Shock Protein 72 (Hsp72) alters glucose homeostasis and the possible approaches to modulating Hsp72 expression. A summation of the role of chemical chaperones in metabolic disorders is also included. Major Conclusions: Targeted manipulation of Hsp72 or use of chemical chaperiones may have clinical utility in treating metabolic disorders such as insulin resistance and T2DM

Hematopoietic Cell–Restricted Deletion of CD36 Reduces High-Fat Diet–Induced Macrophage Infiltration and Improves Insulin Signaling in Adipose Tissue

OBJECTIVE: The fatty acid translocase and scavenger receptor CD36 is important in the recognition and uptake of lipids. Accordingly, we hypothesized that it plays a role in saturated fatty acid-induced macrophage lipid accumulation and proinflammatory activation. RESEARCH DESIGN AND METHODS: In vitro, the effect of CD36 inhibition and deletion in lipid-induced macrophage inflammation was assessed using the putative CD36 inhibitor, sulfosuccinimidyl oleate (SSO), and bone marrow-derived macrophages from mice with (CD36KO) or without (wild-type) global deletion of CD36. To investigate whether deletion of macrophage CD36 would improve insulin sensitivity in vivo, wild-type mice were transplanted with bone marrow from CD36KO or wild-type mice and then fed a standard or high-fat diet (HFD) for 20 weeks. RESULTS: SSO treatment markedly reduced saturated fatty acid-induced lipid accumulation and inflammation in RAW264.7 macrophages. Mice harboring CD36-specific deletion in hematopoietic-derived cells (HSC CD36KO) fed an HFD displayed improved insulin signaling and reduced macrophage infiltration in adipose tissue compared with wild-type mice, but this did not translate into protection against HFD-induced whole-body insulin resistance. Contrary to our hypothesis and our results using SSO in RAW264.7 macrophages, neither saturated fatty acid-induced lipid accumulation nor inflammation was reduced when comparing CD36KO with wild-type bone marrow-derived macrophages. CONCLUSIONS: Although CD36 does not appear important in saturated fatty acid-induced macrophage lipid accumulation, our study uncovers a novel role for CD36 in the migration of proinflammatory phagocytes to adipose tissue in obesity, with a concomitant improvement in insulin action

The proteoglycan decorin does not influence adiposity, glucose tolerance, or aerobic exercise capacity in mice

Physical activity is associated with improvements in insulin sensitivity and muscle function. The proteoglycan decorin is increased in skeletal muscle and plasma in response to exercise, but the biological implications are unknown. We investigated the effects of decorin deficiency on obesity, glucose tolerance, and exercise adaptation in C57BL/6J mice. Decorin deficiency did not influence adiposity, insulin- and glucose- tolerance, or energy metabolism in obese, high fat diet fed mice (Dcn−/− vs. Dcn+/+). Decorin is abundant in the skeletal muscle extracellular matrix, thus we further compared the skeletal muscle of Dcn−/− and Dcn+/+ littermates. There were no effects on muscle morphology or the expression of metabolic markers. Dcn−/− mice had normal exercise capacity measured as running distance on a treadmill. To study the effects of long-term exercise, mice were housed with access to running wheels. Overall, there were no major differences in voluntary wheel running or skeletal muscle metabolic markers, but Dcn−/− mice had a tendency for reduced running wheel activity compared to Dcn+/+ mice. This was accompanied by a smaller exercise effect on metabolic markers in muscle Dcn−/− mice. Our findings indicate that decorin does not have a major impact on glucose tolerance, metabolic adaptation, or aerobic exercise performance.</p