This is a repository copy of c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis.

1Prostaglandins play fundamental roles in adipose tissue function. While prostaglandin 2 F 2α inhibits adipogenesis, prostaglandin E 2 promotes adipose beiging. PGF 2α and 3 PGE 2 are both inactivated through uptake by the plasma membrane transporter (PGT). 4We hypothesized that inhibiting PGT would increase PGF 2α and PGE 2 levels, thereby 5 reducing white fat expansion and inducing beiging. Consistent with this hypothesis, 6inhibiting PGT in mice on high fat diet via genetic knockout or pharmacological blockade 7 reduced body fat stores and induced thermogenesis at thermoneutrality. Inguinal white 8 adipose tissue (iWAT) of these mice exhibited robust UCP1-independent thermogenesis 9 characterized by mitochondrial expansion, coupling of O 2 consumption to ATP 10 synthesis, and induction of the creatine pathway. Enhanced coupled respiration 11 persisted in PGT-KO iWAT adipocytes in a creatine shuttle-dependent manner. Thus, 12inhibiting PGT increases mitochondrial biogenesis and coupled respiration-each 13 supported by the creatine pathway in a system lacking UCP1 expression-revealing 14PGT as a promising drug target against obesity. 15 16 RESULTS 48 PGT global knockout mice (PGT-KO mice) exhibit a lean phenotype. 49Results from both male and female KO mice are presented without stratification 50 by sex because mice of both sexes exhibited the same metabolic phenotype. PGT-KO 51 mice had elevated urinary PGE 2 and PGF 2α excretion rates, indicating impaired 52 systemic prostaglandin metabolism ( Figure 1A). PGT-KO mice exhibited reductions in 53 waist circumference (Figure 1 B-D), subcutaneous white adipose tissue (WAT) (Figure 1 54 E-F), visceral (gonadal) white adipose tissue (gWAT) (Figure 1 G-I), dermal fat (Figure 1 55 J-L), liver steatosis (Figure 1 M,N), and whole-body fat by echo-MRI composition 56 analysis (Figure 1 O). PGT was differentially expressed in gWAT, iWAT, and 57 interscapular brown adipose tissue (iBAT); compared to WT mice, the masses of these 58 three fat depots in PGT-KO mice were reduced proportional to PGT expression 59 ( Supplementary Figure 1). PGT-KO mice displayed improved glucose tolerance 60 compared to controls ( Figures 1P and Supplementary Figure 1). WAT leptin gene 61 expression, fasting serum leptin, and fasting serum free fatty acids were reduced in 62 PGT-KO mice, whereas fasting serum adiponectin and insulin concentrations were 63 unchanged ( Supplementary Figure 1). Histology revealed that adipocytes of PGT-KO 64 iWAT and iBAT depots were smaller than those of WT mice, and that PGT-KO iWAT 65 contained multilocular adipocytes ( Supplementary Figure 1). 66 PGT-KO mice display increased energy expenditure due to beige induction in the 67iWAT depot. 68Although PGT-KO mice exhibited a 2-fold increase in food intake (Figures 2A 69 and Supplementary Figure 2), there was no difference in stool weight, stool fatty acids, 70

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