Key Points A high frequency of diverse activating mutations in costimulatory/TCR-related signaling genes occurs in AITL and other TFH-derived PTCL. Deregulated TCR activation may play a role in the pathogenesis of TFH-derived PTCL, paving the way for developing novel targeted therapies.

The deleterious effect of chronic activation of the IL-1 system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1 in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1, in a glucose-dependent manner. Subsequently, IL-1 contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1 signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1 and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1 mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium-glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1 and insulin in the regulation of both metabolism and immunity. 30reactive oxygen species production, and NLRP3 inflammasome-mediated IL-1β secretion. 31Post-prandial inflammation is limited by normalization of glycemia and can be prevented by 32 inhibition of sodium-glucose cotransporter 2 (SGLT2). Our findings identify a physiological 33 role for IL-1β and insulin in the regulation of both metabolism and immunity.

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Enteropathy-associated T-cell lymphoma (EATL), a rare and aggressive intestinal malignancy of intraepithelial T lymphocytes, comprises two disease variants (EATL-I and EATL-II) differing in clinical characteristics and pathological features. Here we report findings derived from whole-exome sequencing of 15 EATL-II tumour-normal tissue pairs. The tumour suppressor gene SETD2 encoding a non-redundant H3K36-specific trimethyltransferase is altered in 14/15 cases (93%), mainly by loss-of-function mutations and/or loss of the corresponding locus (3p21.31). These alterations consistently correlate with defective H3K36 trimethylation. The JAK/STAT pathway comprises recurrent STAT5B (60%), JAK3 (46%) and SH2B3 (20%) mutations, including a STAT5B V712E activating variant. In addition, frequent mutations in TP53, BRAF and KRAS are observed. Conversely, in EATL-I, no SETD2, STAT5B or JAK3 mutations are found, and H3K36 trimethylation is preserved. This study describes SETD2 inactivation as EATL-II molecular hallmark, supports EATL-I and -II being two distinct entities, and defines potential new targets for therapeutic intervention.

Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr -/-mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link. IntroductionHepatic glucose metabolism is highly regulated during the fed-tofast transition by changes in plasma levels of insulin and glucagon, but also by the changes in blood glucose concentrations. In the fed state, the presence of high insulin concentrations in the portal circulation favors storage of glucose in the form of glycogen and the use of glucose through the glycolytic pathway for its conversion into fatty acids. Important regulatory events activated during the absorptive phase include the transcriptional induction of glucokinase by insulin and of L-pyruvate kinase by the carbohydrate-responsive element-binding protein (ChREBP), which translocates to the nucleus following its dephosphorylation by a glucose metabolite-activated phosphatase (1). At the same time, glucose inhibits glycogen phosphorylase through inhibition of glycogen phosphorylase phosphatase, whereas glucose-6-phosphate activates glycogen synthase (2), thus favoring glycogen biosynthesis. The combination of insulin-dependent Srebp-1c and glucose-dependent ChREBP activation then induces the expression of lipogenic genes, including Acc, Fas, and Scd1 (1, 3).In the fasted state, the decrease in glycemia reduces the intracellular levels of glucose and glucose-6-phosphate, thereby favoring glycogen degradation and reducing the activation of ChREBP and the expression of L-pyruvate kinase and lipogenic genes. Higher glucagon levels favor the gluconeogenic pathway by inducing the expression of PEPCK and G6Pase that catalyzes the hydrolysis of glucose-6-phosphate into glucose, a reaction that takes place in the lumen of the ER. The last steps of glucose output

How glucose sensing by the nervous system impacts the regulation of β cell mass and function during postnatal development and throughout adulthood is incompletely understood. Here, we studied mice with inactivation of glucose transporter 2 (Glut2) in the nervous system (NG2KO mice). These mice displayed normal energy homeostasis but developed late-onset glucose intolerance due to reduced insulin secretion, which was precipitated by high-fat diet feeding. The β cell mass of adult NG2KO mice was reduced compared with that of WT mice due to lower β cell proliferation rates in NG2KO mice during the early postnatal period. The difference in proliferation between NG2KO and control islets was abolished by ganglionic blockade or by weaning the mice on a carbohydrate-free diet. In adult NG2KO mice, first-phase insulin secretion was lost, and these glucose-intolerant mice developed impaired glucagon secretion when fed a high-fat diet. Electrophysiological recordings showed reduced parasympathetic nerve activity in the basal state and no stimulation by glucose. Furthermore, sympathetic activity was also insensitive to glucose. Collectively, our data show that GLUT2-dependent control of parasympathetic activity defines a nervous system/endocrine pancreas axis that is critical for β cell mass establishment in the postnatal period and for long-term maintenance of β cell function.

PPARβ/δ protects against obesity by reducing dyslipidemia and insulin resistance via effects in muscle, adipose tissue, and liver. However, its function in pancreas remains ill defined. To gain insight into its hypothesized role in β cell function, we specifically deleted Pparb/d in the epithelial compartment of the mouse pancreas. Mutant animals presented increased numbers of islets and, more importantly, enhanced insulin secretion, causing hyperinsulinemia. Gene expression profiling of pancreatic β cells indicated a broad repressive function of PPARβ/δ affecting the vesicular and granular compartment as well as the actin cytoskeleton. Analyses of insulin release from isolated PPARβ/δ-deficient islets revealed an accelerated second phase of glucosestimulated insulin secretion. These effects in PPARβ/δ-deficient islets correlated with increased filamentous actin (F-actin) disassembly and an elevation in protein kinase D activity that altered Golgi organization. Taken together, these results provide evidence for a repressive role for PPARβ/δ in β cell mass and insulin exocytosis, and shed a new light on PPARβ/δ metabolic action.

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