Dataset Information

IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis.

ABSTRACT: Human obesity is associated with decreased circulating adiponectin and elevated leptin levels. In vitro experiments and studies in high fat diet (HFD)-fed mice suggest that interleukin-6 (IL-6) may regulate adiponectin and leptin release from white adipose tissue (WAT). Herein, we aimed to investigate whether IL-6 receptor blockade affects the levels of circulating adiponectin and leptin in obese human individuals. To this end, serum samples collected during a multicenter, double-blind clinical trial were analyzed. In the latter study, obese human subjects with or without type 2 diabetes were randomly assigned to recurrent placebo or intravenous tocilizumab (an IL-6 receptor antibody) administration during a 12-week exercise training intervention. Twelve weeks of tocilizumab administration (in combination with exercise training) trend wise enhanced the decrease in circulating leptin levels (-2.7 ± 8.2% in the placebo vs. -20.6 ± 5.6% in tocilizumab, p = 0.08) and significantly enhanced the increase in circulating adiponectin (3.4 ± 3.7% in the placebo vs. 27.0 ± 6.6% in tocilizumab, p = 0.01). In addition, circulating adiponectin levels were negatively correlated with the homeostatic model assessment of insulin resistance (HOMA-IR), indicating that increased adiponectin levels positively affect insulin sensitivity in people with obesity. In conclusion, IL-6 receptor blockade increases circulating adiponectin levels in people with obesity.

SUBMITTER: Wueest S

PROVIDER: S-EPMC7911215 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis.

Wueest Stephan S Seelig Eleonora E Timper Katharina K Lyngbaek Mark P MP Karstoft Kristian K Donath Marc Y MY Ellingsgaard Helga H Konrad Daniel D

Metabolites 20210129 2

Human obesity is associated with decreased circulating adiponectin and elevated leptin levels. In vitro experiments and studies in high fat diet (HFD)-fed mice suggest that interleukin-6 (IL-6) may regulate adiponectin and leptin release from white adipose tissue (WAT). Herein, we aimed to investigate whether IL-6 receptor blockade affects the levels of circulating adiponectin and leptin in obese human individuals. To this end, serum samples collected during a multicenter, double-blind clinical ...[more]

PMID: 33572989

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Project description:ObjectiveThe steep rise in the prevalence of obesity and its related metabolic syndrome have become a major worldwide health concerns. Melanocortin peptides from hypothalamic arcuate nucleus (Arc) POMC neurons induce satiety to limit food intake. Consequently, Arc Pomc-deficient mice (ArcPomc-/-) exhibit hyperphagia and obesity. Previous studies demonstrated that the circulating levels of adiponectin, a protein abundantly produced and secreted by fat cells, negatively correlate with obesity in both rodents and humans. However, we found that ArcPomc-/- mice have increased circulating adiponectin levels despite obesity. Therefore, we investigated the physiological function and underlying mechanisms of hypothalamic POMC in regulating systemic adiponectin levels.MethodsCirculating adiponectin was measured in obese ArcPomc-/- mice at ages 4-52 weeks. To determine whether increased adiponectin was a direct result of ArcPomc deficiency or a secondary effect of obesity, we examined plasma adiponectin levels in calorie-restricted mice with or without a history of obesity and in ArcPomc-/- mice before and after genetic restoration of Pomc expression in the hypothalamus. To delineate the mechanisms causing increased adiponectin in ArcPomc-/- mice, we determined sympathetic outflow to adipose tissue by assessing epinephrine, norepinephrine, and tyrosine hydroxylase protein levels and measured the circulating adiponectin in the mice after acute norepinephrine or propranolol treatments. In addition, adiponectin mRNA and protein levels were measured in discrete adipose tissue depots to ascertain which fat depots contributed the most to the high level of adiponectin in the ArcPomc-/- mice. Finally, we generated compound Adiopoq-/-:ArcPomc-/- mice and compared their growth, body composition, and glucose homeostasis to the individual knockout mouse strains and their wild-type controls.ResultsObese ArcPomc-/- female mice had unexpectedly increased plasma adiponectin compared to wild-type siblings at all ages greater than 8 weeks. Despite chronic calorie restriction to achieve normal body weights, higher adiponectin levels persisted in the ArcPomc-/- female mice. Genetic restoration of Pomc expression in the Arc or acute treatment of the ArcPomc-/- female mice with melanotan II reduced adiponectin levels to control littermate values. The ArcPomc-/- mice had defective thermogenesis and decreased epinephrine, norepinephrine, and tyrosine hydroxylase protein levels in their fat pads, indicating reduced sympathetic outflow to adipose tissue. Injections of norepinephrine into the ArcPomc-/- female mice reduced circulating adiponectin levels, whereas injections of propranolol significantly increased adiponectin levels. Despite the beneficial effects of adiponectin on metabolism, the deletion of adiponectin alleles in the ArcPomc-/- mice did not exacerbate their metabolic abnormalities.ConclusionIn summary, to the best of our knowledge, this study provides the first evidence that despite obesity, the ArcPomc-/- mouse model has high circulating adiponectin levels, which demonstrated that increased fat mass is not necessarily correlated with hypoadiponectinemia. Our investigation also found a previously unknown physiological pathway connecting POMC neurons via the sympathetic nervous system to circulating adiponectin, thereby shedding light on the biological regulation of adiponectin.

Project description:BackgroundInterleukin-33 (IL-33) plays a pivotal role in regulating innate immune response and metabolic homeostasis. However, whether its circulating level is correlated with obesity and metabolic disorders in humans remains largely unknown. We aimed to address this gap by determining IL-33 serum level and its downstream type 2 inflammatory cytokines interleukin-5 (IL-5) and interleukin-13 (IL-13) in overweight/obese population, and analyzing the specific associations between IL-33 and obesity metabolic phenotypes.Methods217 subjects were enrolled and divided into three groups: healthy control (HC) subjects, metabolically healthy overweight/obese (MHOO) subjects and metabolically unhealthy overweight/obese (MUOO) subjects. Circulating levels of IL-33, IL-5 and IL-13 were measured using ELISA analyses. Multivariate regression analyses were further performed to determine the independent association between IL-33 and obesity metabolic phenotypes.ResultsCirculating levels of IL-33 were significantly elevated in subjects of MUOO group compared with HC group and MHOO group, while no significant difference was observed between the latter two groups in IL-33 levels. Consistent with this, serum levels of IL-5/13 were higher in the MUOO group compared with HC and MHOO groups. After adjusted for all confounders, MUOO phenotype was significantly associated with increased IL-33 serum levels (OR = 1.70; 95% CI 1.09-2.64; p = 0.019). With the MHOO group as the reference population, higher circulating level of IL-33 was also positively associated with MUOO phenotype after adjusting for confounders (OR = 1.50; 95% CI 1.20-1.88; p = 2.91E-4). However, there was no significant association between MHOO phenotype and IL-33 levels (p = 0.942). Trend analysis further confirmed the positive correlation between MUOO phenotype and IL-33 level (p for trend = 0.019). Additionally, IL-33 was significantly and positively correlated with diastolic blood pressure (DBP), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cell (WBC), neutrophil and IL-5 only in MUOO group, while inversely correlated with high density lipoprotein cholesterol (HDL-C) in MHOO subjects.ConclusionCirculating levels of IL-33 were significantly elevated in overweight/obese Chinese adults with metabolic disorders. Increased levels of IL-33 were positively associated with metabolically unhealthy overweight/obese phenotype and several metabolic syndrome risk factors.

Project description:The present meta-analysis was performed to examine the association between circulating blood adipokine levels and Kawasaki disease (KD). Studies were identified by searching various databases, including Web of Science, EMBASE, PubMed, Wanfang and China National Knowledge Infrastructure. After the studies were pooled, the mean difference (MD) and corresponding 95% CI were calculated. Subgroup analyses and publication bias detection were also performed. The Cochrane Q test and I2 statistics were performed using Review Manager software (version 5.3) to test for heterogeneity. A Begg's test was used to assess publication bias and STATA software (version 12.0) was used for statistical analysis. The results revealed that the KD group exhibited higher levels of resistin compared with those in the healthy controls or disease controls (non-KD; MD=20.76, 95% CI=16.16-25.36, P<0.001; MD=21.27, 95% CI=14.24-28.29, P<0.001, respectively). In addition, when compared with those in patients exhibiting non-coronary artery lesions (NCAL), those with coronary artery lesions (CAL) had higher levels of adiponectin and resistin (MD=1.00, 95% CI=0.06-1.96, P=0.04; MD=2.77, 95% CI=1.32-4.22, P<0.001). Furthermore, compared with those in the inactive-phase group, patients in the active-phase group exhibited higher levels of resistin (MD=17.73, 95% CI=12.82-22.65, P<0.001). In conclusion, the present meta-analysis indicated that resistin levels were elevated in patients with KD. It was also revealed that circulating resistin and adiponectin levels in the CAL group were significantly increased compared with those in patients with NCAL. Furthermore, the active group had higher levels of resistin than the inactive group. The results of these meta-analyses indicated that resistin may serve an important role in the pathogenesis of KD and may therefore be used as biomarkers for the diagnosis of KD, whereas adiponectin may only serve an important role in the pathogenesis of CAL and may therefore be used as a biomarker to distinguish CAL from NCAL.

Dataset Information

IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis.

Publications

IL-6 Receptor Blockade Increases Circulating Adiponectin Levels in People with Obesity: An Explanatory Analysis.

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