Divergent dynamics in systemic and tissue-specific metabolic and inflammatory responses during weight loss in subjects with obesity.

AIM: Dysfunction of adipose and muscle tissue associates with obesity-related co-morbidities such as insulin resistance (IR) and inflammation. This study investigates changes in systemic and tissue-specific markers of IR and inflammation after gastric bypass surgery (GBS) in subjects with obesity. METHODS: Prospective study, twenty subjects with obesity (50 ± 10 years, 14 men). Prior to, and six months and one year after GBS, subcutaneous abdominal adipose tissue (SAT), skeletal muscle and fasting serum samples were collected. Serum levels of C-reactive protein (CRP), glucose and insulin were determined using standard laboratory assays and serum IL-6, IL-10 and TNF-α levels were determined using ELISA. Tissue mRNA expression of inflammation and insulin/glucose metabolism markers were analyzed using qPCR. RESULTS: After GBS, HOMA-IR, CRP and IL-6 serum levels decreased. In SAT, expression of bone morphogenetic protein 4 (BMP4), IL-6, IL-10 and MCP1 decreased and GLUT4 increased (all p < 0.05). In muscle, expression of BMP4, GLUT4 and IL-6 decreased and of MCP1 and IRS-1 increased (all p < 0.05). CONCLUSION: Systemic improvements in inflammation and IR after GBS are only partially mirrored by corresponding changes in adipokine and myokine expression patterns. As changes in expression of other markers of inflammation and insulin/glucose metabolism appear less consistent and even divergent between tissues, the inflammatory and IR status at systemic level cannot be extrapolated to the situation in metabolically active tissues.

Insulin resistance associates with hepatic lobular inflammation in subjects with obesity.

PURPOSE: Obese subjects with nonalcoholic fatty liver disease (NAFLD) are more prone to develop additional metabolic disturbances such as systemic insulin resistance (IR) and type 2 diabetes. NAFLD is defined by hepatic steatosis, lobular inflammation, ballooning and stage of fibrosis, but it is unclear if and which components could contribute to IR. OBJECTIVE: To assess which histological components of NAFLD associate with IR in subjects with obesity, and if so, to what extent. METHODS: This cross-sectional study included 78 obese subjects (mean age 46 ± 11 years; BMI 42.2 ± 4.7 kg/m2). Glucose levels were analysed by hexokinase method and insulin levels with electrochemiluminescence. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated. Liver biopsies were evaluated for histological components of NAFLD. RESULTS: A positive association between overall NAFLD Activity Score and HOMA-IR was found (r s = 0.259, P = 0.022). As per individual components, lobular inflammation and fibrosis stage were positively associated with HOMA-IR, glucose and insulin levels (P < 0.05), and HOMA-IR was higher in patients with more inflammatory foci or higher stage of fibrosis. These findings were independent of age, BMI, triglyceride levels, diabetes status and sex (all P < 0.043). In a combined model, lobular inflammation, but not fibrosis, remained associated with HOMA-IR. CONCLUSION: In this group of obese subjects, a major contributing histological component of NAFLD to the relation between NAFLD severity and IR seems to be the grade of hepatic lobular inflammation. Although no causal relationship was assessed, preventing or mitigating this inflammatory response in obesity might be of importance in controlling obesity-related metabolic disturbances.

Determinants of testosterone levels in human male obesity.

Testosterone (T) levels are decreased in obese men, but the underlying causes are incompletely understood. Our objective was to explore the relation between low (free) T levels and male obesity, by evaluating metabolic parameters, subcutaneous adipose tissue (SAT) aromatase expression, and parameters of the hypothalamic-pituitary-gonadal axis. We recruited 57 morbidly obese men [33 had type 2 diabetes (DM2)] and 25 normal-weight men undergoing abdominal surgery. Fourteen obese men also attended a follow-up, 2 years after gastric bypass surgery (GBS). Circulating T levels were quantified by LC-MS/MS, whereas free T levels were measured using serum equilibrium dialysis and sex hormone-binding globulin, luteinizing hormone, and follicle-stimulating hormone by immunoassay. SAT biopsies were used to determine adipocyte cell size and aromatase expression by real-time PCR. Total and free T levels were decreased in obese males versus controls, with a further decrease in obese men with DM2 versus obese men without DM2. There were no differences in aromatase expression among the study groups, and sex steroids did not correlate with aromatase expression. Pearson analysis revealed an inverse association between (free) T and SAT cell size, triglycerides, and HOMA-IR. Multivariate analysis confirmed the inverse association between (free) T and SAT cell size (ß = -0.321, P = 0.037 and ß = -0.441, P = 0.011, respectively), independent of age, triglycerides, HOMA-IR, obesity, or diabetes. T levels were normalized 2 years after GBS. These data suggest that SAT cell size rather than SAT aromatase expression or parameters of the hypothalamic-pituitary-gonadal axis is related to low T in male obesity, which points to adipose cell size-related metabolic changes as a major trigger in decreased T levels.

Immunogenicity and tolerability of intradermal administration of an HCV E1-based vaccine candidate in healthy volunteers and patients with resolved or ongoing chronic HCV infection.

The tolerability and immunogenicity of intradermal injections of a candidate HCV vaccine, based on the E1 protein of the hepatitis C virus (HCV), was examined in an exploratory study in healthy volunteers, in subjects with a history of resolved HCV infection, and in patients suffering from therapy-resistant chronic HCV. Sub-epidermal injection of three doses of 4 microg of non-adjuvanted E1 vaccine induced much weaker humoral and cellular immune responses in healthy subjects and chronic HCV patients than the intramuscular administration of 20 microg E1 formulated on alum. However, in three subjects who cleared HCV infection, intradermal administration of this low dose of E1 induced rapid and clear anamnestic responses. These data demonstrate that E1-specific immune responses can be induced in resolving HCV infections and that memory (B and T) cells can be restimulated with suboptimal doses of E1 antigen.