Macrophage deletion of Noc4l triggers endosomal TLR4/TRIF signal and leads to insulin resistance

In obesity, macrophages drive a low-grade systemic inflammation (LSI) and insulin resistance (IR). The ribosome biosynthesis protein NOC4 (NOC4) mediates 40 S ribosomal subunits synthesis in yeast. Hereby, we reported an unexpected location and function of NOC4L, which was preferentially expressed in human and mouse macrophages. NOC4L was decreased in both obese human and mice. The macrophage-specific deletion of Noc4l in mice displayed IR and LSI. Conversely, Noc4l overexpression by lentivirus treatment and transgenic mouse model improved glucose metabolism in mice. Importantly, we found that Noc4l can interact with TLR4 to inhibit its endocytosis and block the TRIF pathway, thereafter ameliorated LSI and IR in mice.

Obesity Inhibits Angiogenesis Through TWIST1-SLIT2 Signaling

Angiogenesis is required for functional adipose tissue maintenance, remodeling, and expansion. Physiologically balanced adipogenesis and angiogenesis are inhibited in subcutaneous adipose tissue in obese humans. However, the mechanism by which angiogenesis is inhibited in obese adipose tissue is not fully understood. Transcription factor TWIST1 controls angiogenesis and vascular function. TWIST1 expression is lower in obese human adipose tissues. Here, we have demonstrated that angiogenesis is inhibited in endothelial cells (ECs) isolated from adipose tissues of obese humans through TWIST1-SLIT2 signaling. The levels of TWIST1 and SLIT2 are lower in ECs isolated from obese human adipose tissues compared to those from lean tissues. Knockdown of TWIST1 in lean human adipose ECs decreases, while overexpression of TWIST1 in obese adipose ECs restores SLIT2 expression. DNA synthesis and cell migration are inhibited in obese adipose ECs and the effects are restored by TWIST1 overexpression. Obese adipose ECs also inhibit blood vessel formation in the gel subcutaneously implanted in mice, while these effects are restored when gels are mixed with SLIT2 or supplemented with ECs overexpressing TWIST1. These findings suggest that obesity impairs adipose tissue angiogenesis through TWIST1-SLIT2 signaling.

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

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.

Epigallocatechin gallate decreases plasma triglyceride, blood pressure, and serum kisspeptin in obese human subjects

Obesity is one of major risk factors increasing chronic diseases including type II diabetes, cardiovascular diseases, and hypertension. The effects of epigallocatechin gallate (EGCG), the major active compound in green tea, on reduced obesity and improved metabolic profiles are still controversial. Furthermore, the effects of EGCG on human adipocyte lipolysis and browning of white adipocytes have not been elucidated. This study aimed to investigate the effects of EGCG on obesity, lipolysis, and browning of human white adipocytes. The results showed that, when compared to the baseline values, EGCG significantly decreased fasting plasma triglyceride levels ( P < 0.05), systolic blood pressure ( P < 0.05), diastolic blood pressure ( P < 0.05), and serum kisspeptin levels ( P < 0.05) after 8 weeks of supplement. On the other hand, supplement of EGCG in obese human subjects for 4 or 8 weeks did not decrease body weight, body mass index, waist and hip circumferences, nor total body fat mass or percentage when compared to their baseline values. The study in human adipocytes showed that EGCG did not increase the glycerol release when compared to vehicle, suggesting that it had no lipolytic effect. Furthermore, treatment of EGCG did not enhance uncoupling protein 1 ( UCP1) mRNA expression in human white adipocytes when compared with treatment of pioglitazone, the peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, suggesting that EGCG did not augment the browning effect of PPAR-γ on white adipocytes. This study revealed that EGCG reduced 2 metabolic risk factors which are triglyceride and blood pressure in the human experiment. We also showed a novel evidence that EGCG decreased kisspeptin levels. However, EGCG had no effects on obesity reduction in humans, lipolysis, nor browning of human white adipocytes. Impact statement Obesity has become the worldwide problem that causes adverse health consequences in individuals. The effects of EGCG on decreased obesity and improved metabolic profiles are still inconclusive. This study revealed that EGCG decreased 2 metabolic risk factors including blood pressure and triglyceride in human obese subjects but had no effect on obesity reduction. This study also showed a novel finding that EGCG decreased kisspeptin levels in human obese subjects. The study in human adipocytes showed that EGCG had no effects on lipolysis nor browning of human white adipocytes. These findings might suggest that EGCG treatment ameliorated metabolic parameters but did not reduce obesity in obese humans. However, further studies are required to explore the relationship between the effect of EGCG on reduction of blood pressure and kisspeptin levels.