Obesity-Induced Increase in Cystatin C Alleviates Tissue Inflammation.

We recently demonstrated that removal of one kidney (uninephrectomy [UniNx]) in mice reduced high-fat diet (HFD)-induced adipose tissue inflammation, thereby improving adipose tissue and hepatic insulin sensitivity. Of note, circulating cystatin C (CysC) levels were increased in UniNx compared with sham-operated mice. Importantly, CysC may have anti-inflammatory properties, and circulating CysC levels were reported to positively correlate with obesity in humans and as shown here in HFD-fed mice. However, the causal relationship of such observation remains unclear. HFD feeding of CysC-deficient (CysC knockout [KO]) mice worsened obesity-associated adipose tissue inflammation and dysfunction, as assessed by proinflammatory macrophage accumulation. In addition, mRNA expression of proinflammatory mediators was increased, whereas markers of adipocyte differentiation were decreased. Similar to findings in adipose tissue, expression of proinflammatory cytokines was increased in liver and skeletal muscle of CysC KO mice. In line, HFD-induced hepatic insulin resistance and impairment of glucose tolerance were further aggravated in KO mice. Consistently, chow-fed CysC KO mice were more susceptible to lipopolysaccharide-induced adipose tissue inflammation. In people with obesity, circulating CysC levels correlated negatively with adipose tissue Hif1α as well as IL6 mRNA expression. Moreover, healthy (i.e., insulin-sensitive) subjects with obesity had significantly higher mRNA expression of CysC in white adipose tissue. In conclusion, CysC is upregulated under obesity conditions and thereby counteracts inflammation of peripheral insulin-sensitive tissues and, thus, obesity-associated deterioration of glucose metabolism.

Adipocyte-specific gp130 signalling mediates exercise-induced weight reduction.

BACKGROUND: Repetitive physical activity is a well-established intervention to reduce obesity and to prevent weight regain. Besides increased energy expenditure, reduced caloric intake may contribute to exercise-induced weight loss in obesity. Using adipocyte-specific glycoprotein 130 knockout (gp130Δadipo) mice, we recently unravelled that obesity-induced interleukin-6 (IL-6) signalling in adipose tissue contributes to circulating levels of the two anorectic hormones leptin and insulin. Herein, we aimed to investigate the role of adipocyte-specific IL-6 signalling in exercise-mediated appetite control and, hence, weight reduction in obesity. METHODS: gp130Δadipo and control littermate mice (gp130F/F) were repetitively exercised during a 12-week period of HFD-feeding. Thermogenesis was determined using thermography and food intake as well as energy expenditure were assessed in metabolic cages. Circulating IL-6, insulin and leptin levels were measured using immunoassays. Protein levels of phosphorylated STAT3, JAK2 and Akt were determined in the hypothalamus by Western blot technique. RESULTS: Repetitive physical activity reduced food intake and HFD-induced weight gain in gp130F/F but not gp130Δadipo mice. In contrast, energy expenditure was not different between the genotypes. Circulating insulin and leptin levels were significantly reduced in gp130Δadipo mice. Moreover, hypothalamic leptin and insulin signalling were enhanced in exercised gp130F/F but not gp130Δadipo mice as demonstrated by elevated pSTAT3, pJAK2 and pAkt protein levels. CONCLUSION: Adipocyte-specific IL-6 signalling is involved in exercise-mediated regulation of food intake and weight reduction in HFD-fed mice.

Intermittent fasting improves metabolic flexibility in short-term high-fat diet-fed mice.

Four days of high-fat diet (HFD) feeding are sufficient to induce glucose intolerance and hepatic steatosis in mice. While prolonged HFD-induced metabolic complications are partly mediated by increased food intake during the light (inactive) phase, such a link has not yet been established in short-term HFD-fed mice. Herein, we hypothesized that a short bout of HFD desynchronizes feeding behavior, thereby contributing to glucose intolerance and hepatic steatosis. To this end, 12-wk-old C57BL/6J littermates were fed a HFD for 4 days either ad libitum or intermittently. Intermittent-fed mice were fasted for 8 h during their inactive phase. Initiation of HFD led to an immediate increase in food intake already during the first light phase. Moreover, glucose tolerance was significantly impaired in ad libitum- but not in intermittent HFD-fed mice, indicating that desynchronized feeding behavior contributes to short-term HFD-induced glucose intolerance. Of note, overall food intake was similar between the groups, as was body weight. However, intermittent HFD-fed mice revealed higher fat depot weights. Phosphorylation of hormone sensitivity lipase and free fatty acid release from isolated adipocytes were significantly elevated, suggesting increased lipolysis in intermittent HFD-fed mice. Moreover, hepatic mRNA expression of lipogenetic enzymes and liver triglyceride levels were significantly increased in intermittent HFD-fed mice. Importantly, food deprivation decreased respiratory exchange ratio promptly in intermittent- but not in ad libitum HFD-fed mice. In conclusion, retaining a normal feeding pattern prevented HFD-induced impairment of metabolic flexibility in short-term HFD-fed mice.