Daily Endocrinology Research Analysis

UNLABELLED: G protein-coupled receptor 119 (GPR119) is predominantly expressed in pancreatic β-cells, enteroendocrine cells, and the liver. It is a novel therapeutic for dyslipidemia and type 2 diabetes. DA-1241, a GPR119 agonist, improves glucose tolerance by inhibiting gluconeogenesis and enhancing insulin secretion. It mitigates hepatic inflammation by inhibiting NFκB signaling. However, the mechanism by which DA-1241 ameliorates nonalcoholic fatty liver disease (NAFLD) remains unknown. We hypothesized that DA-1241 improves liver steatosis by inducing autophagy in a transcriptional factor EB (TFEB)-dependent manner. It induced autophagy and TFEB nuclear translocation, and decreased lipid content in liver cell lines. Lysotracker staining and DQ-Red BSA assay revealed it increased lysosomal activity. Furthermore, DA-1241 increased the colocalization of mRFP-LC3 and lipid droplets, which were completely abolished by GPR119 knockdown. DA-1241 treatment improved glucose tolerance and insulin sensitivity, reduced liver enzymes activity and hepatic triglyceride levels, and decreased the NAFLD activity score, accompanied by an increased number of autophagosomes and lysosomes in high-fat diet-fed mice. Despite DA-1241 treatment, lysosomal activity and subsequent lipid content reduction were not induced in tfeb knockout HeLa cells. DA-1241 treatment failed to produce favorable metabolic effects, including reduced hepatic triglyceride levels, in liver-specific Tfeb knockout mice. Thus, DA-1241 attenuates hepatic steatosis through TFEB-mediated autophagy induction. ARTICLE HIGHLIGHTS: DA-1241 is a novel small-molecule GPR119 agonist. DA-1241 treatment stimulates autophagy induction and transcriptional factor EB (TFEB) nuclear translocation and subsequently reduces hepatic fat accumulation both in vitro and in vivo. DA-1241 treatment increases the lysosomal activity and colocalization of mRFP-LC3 with lipid droplets. The antisteatotic effect of DA-1241 is offset by GPR119 knockdown or in tfeb knockout HeLa cells and liver-specific Tfeb knockout mice.

KEY POINTS: Activin A is implicated in profibrotic and prosenescent kidney injury and correlates with kidney injury markers in animals and humans. Follistatin, through activin A antagonism, reduces senescence burden, macrophage infiltration, and proinflammatory pathway activation in murine diabetic kidney disease. Follistatin and other antagonists of activin A signaling pathways may be promising, novel therapeutics for diabetic kidney disease. BACKGROUND: Circulating activin A, an inflammatory mediator implicated in profibrotic kidney injury and cellular senescence-induced adipose tissue dysfunction, is increased in human diabetic kidney disease (DKD) and directly correlates with kidney dysfunction. We tested the hypothesis that activin A increases kidney injury, senescent cell abundance, and macrophage infiltration in DKD and antagonism through follistatin (FS) therapy diminishes these effects. METHODS: An accelerated nephropathy type 2 diabetes (db/db) mouse model was generated by implantation of angiotensin II-loaded osmotic minipumps resulting in increased albuminuria and glomerular and tubular injury. Kidney repair effects of FS (5 RESULTS: Activin A antagonism with FS reduced senescence (p19), proinflammatory (including senescence-associated secretory phenotype), and profibrotic markers including activin A. FS improved kidney morphology, restored podocyte markers (nephrin and Wilms tumor-1), and reduced kidney injury biomarkers, albuminuria and kidney fibrosis. FS decreased kidney macrophage and leukocyte infiltration and absent in melanoma 2 inflammasome activation. FS seemed to suppress inflammation through the toll-like receptor-4/NF kappa-light-chain-enhancer of activated B cells pathway CONCLUSIONS: Activin A is a mediator of kidney injury through macrophage-associated inflammation in murine DKD. FS acts through senomorphic activities which inhibit profibrotic, proinflammatory, and prosenescence signaling by activin A. Hence, antiactivin targeting may aid in the development of a promising, novel therapeutic for DKD.

Delta-like ligand 3 (DLL3) is frequently expressed in pulmonary small cell neuroendocrine carcinoma (SCNEC) and has emerged as a promising therapeutic target. However, limited data on DLL3 expression in other neuroendocrine neoplasms (NEN), such as extrapulmonary SCNEC, large cell neuroendocrine carcinomas (LCNEC), mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), gastroenteropancreatic neuroendocrine tumours (GEP-NET), and pulmonary carcinoids, impedes an estimation if other types of NEN might be suitable candidates for anti-DLL3 therapies. We evaluated DLL3 expression in 1294 NEN and 479 non-neuroendocrine carcinomas, correlating the findings with histological subtypes, tumour localisation, and overall survival (OS). Furthermore, we explored the concordance of DLL3 expression during metastatic progression in 67 paired primary NEN and metastases. DLL3 expression was significantly higher in NEC (64.0%) compared to GEP-NET and pulmonary carcinoids (10.1%, p < 0.001), particularly in SCNEC (80.4%), followed by LCNEC (62.6%) and MiNEN (28.6%). DLL3 was common in pulmonary carcinoids (41.5%), but rare in GEP-NET (5.1%) and non-neuroendocrine carcinomas (1.3%). Overall DLL3 expression was highly concordant between metastases and corresponding primary NEN (92.5%, p < 0.001). In univariable analyses, DLL3-expressing pulmonary carcinoids (p = 0.005) and GEP-NET (p = 0.018) were associated with decreased OS, but this was not retained in multivariable analyses adjusting for stage and grade (p = n. s.). No prognostic impact was observed in pulmonary (p = 0.708) or GEP-NEC (p = 0.87). Our study highlights significant differences in DLL3 expression across NEN subtypes and localisations, with largely concordant expression in metastases. DLL3-based therapies may be effective in many NEC and pulmonary carcinoids, while DLL3 appears to be a minor therapeutic target for GEP-NET and non-neuroendocrine carcinomas.