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

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 to 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 herein in HFD-fed mice. However, the causal relationship of such observation remains unclear. HFD feeding of CysC-deficient (CysC KO) mice deteriorated obesity-associated adipose tissue inflammation and dysfunction, as assessed by pro-inflammatory macrophage accumulation. In addition, mRNA expression of pro-inflammatory mediators was increased, whereas markers of adipocyte differentiation were decreased. Similarly to findings in adipose tissue, expression of pro-inflammatory 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 knockout mice. Consistently, chow-fed CysC KO mice were more susceptible to lipopolysaccharide (LPS)-induced adipose tissue inflammation. In people with obesity, circulating CysC levels correlated negatively with adipose tissue Hif1α as well as IL-6 mRNA expression. Moreover, healthy (i.e. insulin-sensitive) subjects with obesity depicted 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