We developed MEBOCOST, a computational algorithm for quantitatively inferring metabolite-mediated intercellular communications using single cell RNA-seq data. The algorithm identifies cell-cell communications in which metabolites, such as lipids, are secreted by sender cells and traveled to interact with sensor proteins of receiver cells. The sensor proteins on receiver cell might be cell surface receptors, transporters across the cell membrane, or nuclear receptors. MEBOCOST relies on a comprehensive database of metabolite-sensor partners, which we manually curated from the literatures and other public sources. MEBOCOST defines sender and receiver cells for an extracellular metabolite based on the expression levels of the enzymes and sensors, respectively, thus identifies metabolite-sensor communications between the cells. Applying MEBOCOST to mouse brown adipose tissue (BAT) successfully recaptured known metabolite-mediated cell communications and further identified new communications. Additionally, MEBOCOST identified a set of BAT intercellular metabolite-sensor communications that was regulated by cold exposure of the mice. MEBOCOST will be useful to numerous researchers to investigate metabolite-mediated cell-cell communications in many biological and disease models. The MEBOCOST software is freely available at https://github.com/zhengrongbin/MEBOCOST .

N⁶-methyladenosine (m⁶A) is among the most abundant mRNA modifications, yet its cell-type-specific regulatory roles remain unclear. Here we show that m⁶A methyltransferase-like 14 (METTL14) differentially regulates transcriptome in brown versus white adipose tissue (BAT and WAT), leading to divergent metabolic outcomes. In humans and mice with insulin resistance, METTL14 expression differs significantly from BAT and WAT in the context of its correlation with insulin sensitivity. Mettl14-knockout in BAT promotes prostaglandin secretion, improving systemic insulin sensitivity. Conversely, Mettl14-knockout in WAT triggers adipocyte apoptosis and systemic insulin resistance. m⁶A-seq and RNA-seq integration revealed upregulated prostaglandin biosynthesis pathways in BAT and apoptotic pathways in WAT with Mettl14 deficiency. Stable METTL14-knockout hBAs/hWAs show METTL14-mediated m⁶A promotes mRNA decay of PTGES2 and CBR1 in hBAs and TRAIL and TNFR1 in hWAs. These data shed light on the ability of m⁶A to impact metabolism in a cell-type-specific manner with implications for influencing the pathophysiology of metabolic diseases.

Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.

The orexins (orexin-A and orexin-B) are neuropeptides that are secreted from neurons in the lateral hypothalamus and that participate in the regulation of feeding behavior. It remains to be determined, however, how the orexins exert their effects on feeding behavior, including masticatory movements. To this end, we analyzed food intake behavior and masticatory muscle activity using video analysis and electromyography (EMG) recording methods. The results showed that the cumulative food intake over 4 h was larger in rats intraventricularly injected with either orexin-A or orexin-B than in saline-injected control rats. The latency to eating and the feeding time for a fixed amount of pellets were shortened by injections of orexins in a dose-dependent manner, with a more potent effect by orexin-A than orexin-B. The shorter feeding time corresponded to a decreased number of chewing cycles. EMG recordings from both the digastric and masseter muscles showed two distinct patterns of bursts corresponding to the gnawing and chewing phases. After the injection of orexin-A, the magnitude of the bursts became larger in both phases in the masseter muscle, the burst duration became longer in the chewing phase in the masseter muscle, and the interburst interval became shortened in the gnawing phase in both muscles. Consequently, the burst frequency in the chewing phase was increased in the digastric muscle and, conversely, reduced in the masseter muscle. These results suggest that the orexin-A-induced facilitatory feeding behavior is characterized by a dynamic jaw-opener activity that opens the mouth rapidly and a powerful jaw-closer activity for crushing the increased amount of food taken into the mouth. The possible involvement of orexin-A in binge eating disorder is discussed.