Suppression of α/β-domain hydrolase-6 (ABHD6), a monoacylglycerol (MAG) hydrolase, promotes glucose-stimulated insulin secretion by pancreatic β cells. We report here that high-fat-diet-fed ABHD6-KO mice show modestly reduced food intake, decreased body weight gain and glycemia, improved glucose tolerance and insulin sensitivity, and enhanced locomotor activity. ABHD6-KO mice also show increased energy expenditure, cold-induced thermogenesis, brown adipose UCP1 expression, fatty acid oxidation, and white adipose browning. Adipose browning and cold-induced thermogenesis are replicated by the ABHD6 inhibitor WWL70 and by antisense oligonucleotides targeting ABHD6. Our evidence suggests that one mechanism by which the lipolysis derived 1-MAG signals intrinsic and cell-autonomous adipose browning is via PPARα and PPARγ activation, and that ABHD6 regulates adipose browning by controlling signal competent 1-MAG levels. Thus, ABHD6 regulates energy homeostasis, brown adipose function, and white adipose browning and is a potential therapeutic target for obesity and type 2 diabetes.

The present data suggest that, as demonstrated for footshock-induced reinstatement of drug seeking, brain CRF, but not corticosterone, plays a critical role in acute food-deprivation-induced reinstatement of heroin seeking.

When more really means more: WGS standards and quality control Next-generation sequencing (NGS) is reshaping the landscape of modern genetic diagnostic laboratories and their operational standards. NGS is gradually replacing the single-gene Sanger sequencing with targeted multigene panel-based resequencing for genes with variants implicated in any number of common diseases, from cardiovascular or neurological disorders to cancers or drug treatment response. Further advances in technology are positioning whole exome and ultimately whole genome sequencing (WES and WGS) for common diagnostic use. In a rapidly changing environment, quality control considerations are crucial. In this issue, Stephan White et al. (Hum Mutat 38: 912-921, 2017) discuss the critical steps that are required to properly perform WGS. They emphasize the key differences between WGS and WES, the important variables that need to be taken into serious consideration when performing NGS for both germline and somatic variants, the necessary quality control measures to monitor the entire process, and the standard operation procedures to ensure that NGS services will always be provided in a standardized manner. It is obvious that further technological advances in massively parallel DNA sequencing technology, accompanied by concomitant price reductions, will make WES and WGS more affordable and hence easier to become the ultimate genetic test in molecular diagnosis. Such advances must undoubtedly be accompanied with the necessary health technology assessment and economic evaluation analyses, demonstrating that such approaches are indeed cost-effective so that they can be adopted sooner and, most importantly, are covered by national healthcare systems. The points discussed in White et al., combined with those from recently published guidelines for variant calling, genomic databases, genomic data sharing and translational tools, should facilitate implementation of NGS services into the molecular diagnostic setting for routine clinical care.

α/β-Hydrolase domain 6 (ABHD6) is a monoacylglycerol hydrolase that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Although complete or peripheral ABHD6 loss of function is protective against diet-induced obesity and insulin resistance, the role of ABHD6 in the central control of energy balance is unknown. Using a viral-mediated knockout approach, targeted endocannabinoid measures, and pharmacology, we discovered that mice lacking ABHD6 from neurons of the ventromedial hypothalamus (VMH) have higher VMH 2-AG levels in conditions of endocannabinoid recruitment and fail to physiologically adapt to key metabolic challenges. VMH mice exhibited blunted fasting-induced feeding and reduced food intake, energy expenditure, and adaptive thermogenesis in response to cold exposure, high-fat feeding, and dieting (transition to a low-fat diet). Our findings identify ABHD6 as a regulator of the counter-regulatory responses to major metabolic shifts, including fasting, nutrient excess, cold, and dieting, thereby highlighting the importance of ABHD6 in the VMH in mediating energy metabolism flexibility.

Cell therapy has received significant attention as a therapeutic approach to restore cardiac function after myocardial infarction. Accumulating evidence supports that beneficial effects observed with cell therapy are due to paracrine secretion of multiple factors from transplanted cells, which alter the tissue microenvironment and orchestrate cardiac repair processes. Of these paracrine factors, extracellular vesicles (EVs) have emerged as a key effector of cell therapy. EVs regulate cellular function through the transfer of cargo, such as microRNAs and proteins, which act on multiple biological pathways within recipient cells. These discoveries have led to the development of cell-free therapies using EVs to improve cardiac repair after a myocardial infarction. Here, we present an overview of the current use of EVs to enhance cardiac repair after myocardial infarction. We also discuss the emerging use of EVs for rejuvenation-based therapies. Finally, future directions for the use of EVs as therapeutic agents for cardiac regenerative medicine are also discussed.