PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity.

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance

Three-dimensional urban thermal effect across a large city cluster during an extreme heat wave: observational analysis

Given extensive and rapid urbanization globally, assessing regional urban thermal effects (UTE) in both canopy and boundary layers under extreme weather/climate conditions is of significant interest. Rapid population and economic growth in the Yangtze River Delta (YRD) have made it one of the largest city clusters in China. Here, we explore the three-dimensional (3D) UTE in the YRD using multi-source observations from high-resolution automatic weather stations, radiosondes, and eddy covariance sensors during the record-setting heat wave (HW) of July–August 2013. It is found that the regional canopy layer UTE is up to 0.6–1.2°C, and the nocturnal UTE (0.7–1.6°C) is larger than daytime UTE (0.2–0.5°C) during the HW. The regional canopy layer UTE is enhanced and expanded northwards, with some rural sites contaminated by the urban influences, especially at night. In the boundary layer, the strengthened regional UTE extends vertically to at least 925 hPa (∼750 m) during this HW. The strengthened 3D UTE in the YRD is associated with an enlarged Bowen ratio difference between urban and non-urban areas. These findings about the 3D UTE are beneficial for better understanding of the thermal environment of large city clusters under HW and for more appropriate adaption and mitigation strategies

ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway in breast cancer.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer stimulator of interferon genes (STING) pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single-cell RNA-seq, we show that ENPP1 in both cancer and normal tissues drives primary breast tumor growth and metastasis by dampening extracellular 23-cyclic-GMP-AMP (cGAMP)-STING-mediated antitumoral immunity. ENPP1 loss-of-function in both cancer cells and normal tissues slowed primary tumor growth and abolished metastasis. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied ENPP1 knockout in a STING-dependent manner, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Finally, ENPP1 expression in breast tumors deterministically predicated whether patients would remain free of distant metastasis after pembrolizumab (anti-PD-1) treatment followed by surgery. Altogether, ENPP1 blockade represents a strategy to exploit cancer-produced extracellular cGAMP for controlled local activation of STING and is therefore a promising therapeutic approach against breast cancer

A gel-like condensation of Cidec generates lipid-permeable plates for lipid droplet fusion

Membrane contact between intracellular organelles is important in mediating organelle communication. However, the assembly of molecular machinery at membrane contact site and its internal organization correlating with its functional activity remain unclear, Here, we demonstrate that a gel-like condensation of Cidec, a crucial protein for obesity development by facilitating lipid droplet (LD) fusion, occurs at the LD-LD contact site (LDCS) through phase separation. The homomeric interaction between the multivalent N terminus of Cidec is sufficient to promote its phase separation both in vivo and in vitro. Interestingly, Cidec condensation at LDCSs generates highly plastic and lipid-permeable fusion plates that are geometrically constrained by donor LDs. In addition, Cidec condensates are distributed unevenly in the fusion plate generating stochastic sub-compartments that may represent unique lipid passageways during LD fusion. We have thus uncovered the organization and functional significance of geometry-constrained Cidec phase separation in mediating LD fusion and lipid homeostasis

An exercise-inducible metabolite that suppresses feeding and obesity

Exercise confers robust protection against obesity, type 2 diabetes, and other cardiometabolic diseases.(1–5) However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear.(6) Here we show that exercise stimulates production of Lac-Phe, a blood-borne signaling metabolite that suppresses feeding and obesity. Lac-Phe biosynthesis from lactate occurs in CNDP2+ cells including immune cells, epithelial cells, and mesenchymal stem cells localized to diverse organs. In diet-induced obese mice, pharmacological elevation of circulating Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Lastly, dramatic activity-inducible elevations of circulating Lac-Phe levels are also observed in humans and racehorses, establishing this metabolite to be a robust molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance