BCAA catabolism in brown fat controls energy homeostasis through SLC25A44.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health

Comparison of insulin glargine 300 U/mL and insulin degludec using flash glucose monitoring: A randomized cross‐over study

Abstract Aims/Introduction We compared the efficacy and safety of insulin glargine 300 U/mL (Gla300) and insulin degludec U100 (Deg) using a flash glucose monitoring system. Materials and Methods A total of 24 Japanese patients with type 2 diabetes were randomized to receive once‐daily Gla300 (n = 12) or Deg (n = 12) in the morning. The primary end‐points were the mean percentage of time in the target glucose range (70–179 mg/dL) and hypoglycemia (<70 mg/dL), as measured using flash glucose monitoring during the last 7 days of each 14‐day period. Results The percentages of time with glucose levels <70 mg/dL were not significantly different between the two insulin treatments. No significant differences were observed in the percentages of time with glucose levels of 70–179 mg/dL or ≥180 mg/dL. The percentage of time with nocturnal hypoglycemia with Gla300 was significantly lower than that with Deg treatment (P = 0.021). This difference might be attributable to the difference in the duration of action between the two formulations, and the incidence of nocturnal hypoglycemia with Deg treatment was associated with the concomitant use of metformin (P = 0.035). Conclusions The two formulations were comparable in efficacy, whereas the incidence of nocturnal hypoglycemia was significantly lower with Gla300. Thus, the present study suggests that, although Gla300 and Deg are comparable long‐acting insulin analogs, Gla300 is safer with respect to the incidence of hypoglycemia

Roles of Gut-Derived Secretory Factors in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Their Possible Clinical Applications

The rising prevalence of non-alcoholic fatty liver disease (NAFLD) parallels the global increase in the number of people diagnosed with obesity and metabolic syndrome. The gut-liver axis (GLA) plays an important role in the pathogenesis of NAFLD/non-alcoholic steatohepatitis (NASH). In this review, we discuss the clinical significance and underlying mechanisms of action of gut-derived secretory factors in NAFLD/NASH, focusing on recent human studies. Several studies have identified potential causal associations between gut-derived secretory factors and NAFLD/NASH, as well as the underlying mechanisms. The effects of gut-derived hormone-associated drugs, such as glucagon-like peptide-1 analog and recombinant variant of fibroblast growth factor 19, and other new treatment strategies for NAFLD/NASH have also been reported. A growing body of evidence highlights the role of GLA in the pathogenesis of NAFLD/NASH. Larger and longitudinal studies as well as translational research are expected to provide additional insights into the role of gut-derived secretory factors in the pathogenesis of NAFLD/NASH, possibly providing novel markers and therapeutic targets in patients with NAFLD/NASH

Activation of Classical Brown Adipocytes in the Adult Human Perirenal Depot Is Highly Correlated with PRDM16–EHMT1 Complex Expression

<div><p>Brown fat generates heat to protect against cold and obesity. Adrenergic stimulation activates the thermogenic program of brown adipocytes. Although the bioactivity of brown adipose tissue in adult humans had been assumed to very low, several studies using positron emission tomography–computed tomography (PET–CT) have detected bioactive brown adipose tissue in adult humans under cold exposure. In this study, we collected adipose tissues obtained from the perirenal regions of adult patients with pheochromocytoma (PHEO) or non-functioning adrenal tumors (NF). We demonstrated that perirenal brown adipocytes were activated in adult patients with PHEO. These cells had the molecular characteristics of classical brown fat rather than those of beige/brite fat. Expression of brown adipose tissue markers such as uncoupling protein 1 (UCP1) and cell death-inducing DFFA-like effector A (CIDEA) was highly correlated with the amounts of PRD1-BF-1-RIZ1 homologous domain-containing protein-16 (PRDM16) – euchromatic histone-lysine N-methyltransferase 1 (EHMT1) complex, the key transcriptional switch for brown fat development. These results provide novel insights into the reconstruction of human brown adipocytes and their therapeutic application against obesity and its complications such as type 2 diabetes.</p></div

Subject characteristics.

<p>Comparisons between the NF and PHEO groups.</p><p>Values are the means ± SEM, median (interquartile range), number, or <i>P</i>-value.</p><p>*Values were normalized by logarithmic conversion before comparisons.</p><p>Subject characteristics.</p

The PRDM16–EHMT1 complex plays an important role in the adult human brown adipose cell development.

<p>(A, B) Correlation analyses at the mRNA level were performed in tissues from patients with PHEO between <i>PRDM16</i> (A) or <i>EHMT1</i> (B) and BAT-associated genes (left to right, <i>UCP1</i>, <i>PPARGC1A</i>, <i>CIDEA</i>, and <i>ELOVL3</i>). (C, D) The correlation was also assessed at the protein level between PRDM16 and UCP1 (C, left), PRDM16 and CIDEA (C, right), EHMT1 and UCP1 (D, left), or EHMT1 and CIDEA (D, right). Protein expression levels were assessed by western blot analysis (shown in Fig. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122584#pone.0122584.g001" target="_blank">1E</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122584#pone.0122584.g003" target="_blank">3E</a>). (F) Correlation between the PRDM16 protein and EHMT1 protein in PHEO samples. The protein expression levels were assessed by western blot analysis (E).</p

The expression levels of BAT-associated genes are not affected by clinical characteristics.

<p>(A) The correlation matrix between BAT-associated gene expression (top to bottom: UCP1, CIDEA, PPARGC1A, or ELOVL3) and subject characteristics (left to right: age, gender, body mass index (BMI), and total preoperative urinary catecholamine levels) in patients with NF (cross) or PHEO (circle). (B) Correlation analysis between individual urinary catecholamines and <i>UCP1</i> mRNA. *Values were normalized by logarithmic transformation before each correlation analysis.</p