Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insulin resistance (IR). While ERα seems to have a protective role in such diseases, the function of ERβ is not clear. To characterize the metabolic function of ERβ, we investigated its molecular interaction with a master regulator of insulin signaling/glucose metabolism, the PPARγ, in vitro and in high-fat diet (HFD)-fed ERβ -/- mice (βERKO) mice. Our in vitro experiments showed that ERβ inhibits ligand-mediated PPARγ-transcriptional activity. That resulted in a blockade of PPARγ-induced adipocytic gene expression and in decreased adipogenesis. Overexpression of nuclear coactivators such as SRC1 and TIF2 prevented the ERβ-mediated inhibition of PPARγ activity. Consistent with the in vitro data, we observed increased PPARγ activity in gonadal fat from HFD-fed βERKO mice. In consonance with enhanced PPARγ activation, HFD-fed βERKO mice showed increased body weight gain and fat mass in the presence of improved insulin sensitivity. To directly demonstrate the role of PPARγ in HFD-fed βERKO mice, PPARγ signaling was disrupted by PPARγ antisense oligonucleotide (ASO). Blockade of adipose PPARγ by ASO reversed the phenotype of βERKO mice with an impairment of insulin sensitization and glucose tolerance. Finally, binding of SRC1 and TIF2 to the PPARγ-regulated adiponectin promoter was enhanced in gonadal fat from βERKO mice indicating that the absence of ERβ in adipose tissue results in exaggerated coactivator binding to a PPARγ target promoter. Collectively, our data provide the first evidence that ERβ-deficiency protects against diet-induced IR and glucose intolerance which involves an augmented PPARγ signaling in adipose tissue. Moreover, our data suggest that the coactivators SRC1 and TIF2 are involved in this interaction. Impairment of insulin and glucose metabolism by ERβ may have significant implications for our understanding of hormone receptor-dependent pathophysiology of metabolic diseases, and may be essential for the development of new ERβ-selective agonists.

Abstract-Two active metabolites of the angiotensin type 1 (AT 1 ) receptor blocker losartan have been described previously, EXP3174 and EXP3179. Whereas EXP3174 is the main antihypertensive AT 1 receptor-blocking metabolite, the role of EXP3179 is widely unknown. Recently, a subgroup of AT 1 receptor blockers has been identified as ligands for the peroxisome proliferator-activated receptor ␥ (PPAR-␥ he Losartan Intervention For End point reduction in hypertension (LIFE) study has shown that hypertensive patients receiving the angiotensin type 1 receptor blocker (ARB) losartan have a 25% lower rate of new-onset diabetes than patients treated with the ␤-blocker atenolol. 1 Although these data suggest a possible antidiabetic action of losartan, the molecular mechanisms are widely unknown.We and others recently demonstrated that a subset of ARBs, including losartan, induces the activity of a nuclear hormone receptor named peroxisome proliferator-activated receptor ␥ (PPAR-␥) by partial agonism. 2,3 The direct activation of the ligand-binding domain of PPAR-␥ by ARBs is independent of their angiotensin type 1 receptor (AT 1 R) blocking actions. 3 PPAR-␥ functions as a transcriptional regulator in adipose tissue where it regulates multiple genes involved in lipid and glucose metabolism. 4 Activated by synthetic full agonists like thiazolidinediones/glitazones, PPAR-␥ markedly improves whole-body insulin sensitivity resulting in decreased levels of fasting plasma glucose, fasting plasma insulin, and plasma triglycerides. 5 Thus, PPAR-␥ activation by ARBs presents a promising molecular mechanism for metabolic actions of these compounds.Losartan induced PPAR-␥ activity only at high concentrations in vitro. 3 Losartan is hepatically metabolized by the cytochrome-P450 pathway and exerts its antihypertensive actions in vivo predominantly by its main metabolite, EXP3174 (Figure 1). 6,7 During hepatic metabolization of losartan, additional active metabolites are produced, including EXP3179 (Figure 1). This metabolite has a significant molecular homology with indomethacin, an antiinflammatory cyclooxygenase (COX) inhibitor, and mediates a variety of AT 1 R-independent, pleiotropic functions (eg, inhibition of platelet aggregation, endothelial adhesion molecule expression, etc). 7 Indomethacin has been also identified as an activator of PPAR-␥. 8 Given the structural homology of indomethacin and EXP3179, it is likely that EXP3179 has

plus concurrent chemoradiation therapy (cCRT) may provide treatment benefit to patients with locally advanced, stage III non-small cell lung cancer (NSCLC).OBJECTIVE To evaluate treatment outcomes and safety of pembrolizumab plus cCRT in stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTSThe phase 2, nonrandomized, 2-cohort, open-label KEYNOTE-799 study enrolled patients between November 5, 2018, and July 31, 2020, from 52 academic facilities and community-based institutions across 10 countries. As of October 28, 2020, median (range) follow-up was 18.5 (13.6-23.8) months in cohort A and 13.7 (2.9-23.5) months in cohort B. Of 301 patients screened, 216 eligible patients with previously untreated, unresectable, and pathologically/radiologically confirmed stage IIIA/IIIB/IIIC NSCLC with measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) were enrolled.INTERVENTIONS Patients in cohort A (squamous/nonsquamous) received 1 cycle (3 weeks) of carboplatin (area under the curve [AUC] 6 mg/mL/min), paclitaxel (200 mg/m 2 ), and pembrolizumab (200 mg), followed by carboplatin (AUC 2 mg/mL/min) and paclitaxel (45 mg/m 2 ) once weekly for 6 weeks and 2 cycles of pembrolizumab plus standard thoracic radiotherapy. Patients in cohort B (nonsquamous) received 3 cycles of cisplatin (75 mg/m 2 ), pemetrexed (500 mg/m 2 ), and pembrolizumab (200 mg) every 3 weeks and thoracic radiotherapy in cycles 2 and 3. Patients received 14 additional cycles of pembrolizumab. MAIN OUTCOMES AND MEASURESCoprimary end points were objective response rate per RECIST v1.1 by blinded independent central review and incidence of grade 3 to 5 pneumonitis. RESULTS A total of 112 patients received treatment in cohort A (76 men [67.9%]; median [range] age, 66.0 [46-90] years; 66 patients [58.9%] with programmed cell death ligand 1 [PD-L1] tumor proportion score Ն1%) and 102 patients received treatment in cohort B (62 men [60.8%]; median [range] age, 64.0 [35-81] years; 40 patients [39.2%] with PD-L1 tumor proportion score Ն1%). Objective response rate was 70.5% (79 of 112; 95% CI, 61.2%-78.8%) in cohort A and 70.6% (72 of 102; 95% CI, 60.7%-79.2%) in cohort B.Median duration of response was not reached, but 79.7% and 75.6%, respectively, had response duration of 12 months or longer. Grade 3 or higher pneumonitis occurred in 9 of 112 patients (8.0%) in cohort A and 7 of 102 (6.9%) in cohort B. Grade 3 to 5 treatment-related adverse events occurred in 72 of 112 (64.3%) and 51 of 102 (50.0%) patients, respectively. CONCLUSIONS AND RELEVANCEThe findings of this phase 2, nonrandomized, 2-cohort study suggest promising antitumor activity of pembrolizumab plus cCRT and manageable safety in patients with previously untreated, locally advanced, stage III NSCLC.

OBJECTIVE-The angiotensin type 1 receptor blocker (ARB) and peroxisome proliferator-activated receptor (PPAR) ␥ modulator telmisartan has been recently demonstrated to reduce plasma triglycerides in nondiabetic and diabetic hypertensive patients. The present study investigates the molecular mechanisms of telmisartans hypolipidemic actions, in particular its effect on the PPAR␣ pathway.RESEARCH DESIGN AND METHODS-Regulation of PPAR␣ target genes by telmisartan was studied by real-time PCR and Western immunoblotting in vitro and in vivo in liver/skeletal muscle of mice with diet-induced obesity. Activation of the PPAR␣ ligand binding domain (LBD) was investigated using transactivation assays.RESULTS-Telmisartan significantly induced the PPAR␣ target genes carnitine palmitoyl transferase 1A (CPT1A) in human HepG2 cells and acyl-CoA synthetase long-chain family member 1 (ACSL1) in murine AML12 cells in the micromolar range. Telmisartan-induced CPT1A stimulation was markedly reduced after small interfering RNA-mediated knockdown of PPAR␣. Telmisartan consistently activated the PPAR␣-LBD as a partial PPAR␣ agonist. Despite high in vitro concentrations required for PPAR␣ activation, telmisartan (3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) potently increased ACSL1 and CPT1A expression in liver from dietinduced obese mice associated with a marked decrease of hepatic and serum triglycerides. Muscular CPT1B expression was not affected. Tissue specificity of telmisartan-induced PPAR␣ target gene induction may be the result of previously reported high hepatic concentrations of telmisartan.CONCLUSIONS-The present study identifies the ARB/PPAR␥ modulator telmisartan as a partial PPAR␣ agonist. As a result of its particular pharmacokinetic profile, PPAR␣ activation by telmisartan seems to be restricted to the liver. Hepatic PPAR␣ activation may provide an explanation for telmisartan's antidyslipidemic actions observed in recent clinical trials.

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