Publications

2020

Pradas-Juni M, Hansmeier NR, Link JC, Schmidt E, Larsen BD, Klemm P, Meola N, Topel H, Loureiro R, Dhaouadi I, et al. A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism. Nature communications. 2020;11(1):644. doi:10.1038/s41467-020-14323-y

Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcripts with elusive functions in metabolism. Here we show that a high fraction of lncRNAs, but not protein-coding mRNAs, are repressed during diet-induced obesity (DIO) and refeeding, whilst nutrient deprivation induced lncRNAs in mouse liver. Similarly, lncRNAs are lost in diabetic humans. LncRNA promoter analyses, global cistrome and gain-of-function analyses confirm that increased MAFG signaling during DIO curbs lncRNA expression. Silencing Mafg in mouse hepatocytes and obese mice elicits a fasting-like gene expression profile, improves glucose metabolism, de-represses lncRNAs and impairs mammalian target of rapamycin (mTOR) activation. We find that obesity-repressed LincIRS2 is controlled by MAFG and observe that genetic and RNAi-mediated LincIRS2 loss causes elevated blood glucose, insulin resistance and aberrant glucose output in lean mice. Taken together, we identify a MAFG-lncRNA axis controlling hepatic glucose metabolism in health and metabolic disease.

Zheng J, Alves-Wagner AB, Stanford KI, Prince NB, So K, Mul JD, Dirice E, Hirshman MF, Kulkarni RN, Goodyear LJ. Maternal and paternal exercise regulate offspring metabolic health and beta cell phenotype. BMJ open diabetes research & care. 2020;8(1). doi:10.1136/bmjdrc-2019-000890

OBJECTIVE: Poor maternal and paternal environments increase the risk for obesity and diabetes in offspring, whereas maternal and paternal exercise in mice can improve offspring metabolic health. We determined the effects of combined maternal and paternal exercise on offspring health and the effects of parental exercise on offspring pancreas phenotype, a major tissue regulating glucose homeostasis.

RESEARCH DESIGN AND METHODS: Breeders were high fat fed and housed±running wheels before breeding (males) and before and during gestation (females). Offspring groups were: both parents sedentary (Sed); maternal exercise only (Mat Ex); paternal exercise only (Pat Ex); and maternal+paternal exercise (Mat+Pat Ex). Offspring were sedentary, chow fed, and studied at weaning, 12, 20 and 52 weeks.

RESULTS: While there was no effect of parental exercise on glucose tolerance at younger ages, at 52 weeks, offspring of Mat Ex, Pat Ex and Mat+Pat Ex displayed lower glycemia and improved glucose tolerance. The greatest effects were in offspring from parents that both exercised (Mat+Pat Ex). Offspring from Mat Ex, Pat Ex, and Mat+Pat Ex had decreased beta cell size, whereas islet size and beta cell mass only decreased in Mat+Pat Ex offspring.

CONCLUSIONS: Maternal and paternal exercise have additive effects to improve glucose tolerance in offspring as they age, accompanied by changes in the offspring endocrine pancreas. These findings have important implications for the prevention and treatment of type 2 diabetes.

Lee M, Maji B, Manna D, Kahraman S, Elgamal RM, Small J, Kokkonda P, Vetere A, Goldberg JM, Lippard SJ, et al. Native Zinc Catalyzes Selective and Traceless Release of Small Molecules in β-Cells. Journal of the American Chemical Society. 2020;142(14):6477–6482. doi:10.1021/jacs.0c00099

The loss of insulin-producing β-cells is the central pathological event in type 1 and 2 diabetes, which has led to efforts to identify molecules to promote β-cell proliferation, protection, and imaging. However, the lack of β-cell specificity of these molecules jeopardizes their therapeutic potential. A general platform for selective release of small-molecule cargoes in β-cells over other islet cells ex vivo or other cell-types in an organismal context will be immensely valuable in advancing diabetes research and therapeutic development. Here, we leverage the unusually high Zn(II) concentration in β-cells to develop a Zn(II)-based prodrug system to selectively and tracelessly deliver bioactive small molecules and fluorophores to β-cells. The Zn(II)-targeting mechanism enriches the inactive cargo in β-cells as compared to other pancreatic cells; importantly, Zn(II)-mediated hydrolysis triggers cargo activation. This prodrug system, with modular components that allow for fine-tuning selectivity, should enable the safer and more effective targeting of β-cells.

De Jesus DF, Orime K, Kaminska D, Kimura T, Basile G, Wang C-H, Haertle L, Riemens R, Brown NK, Hu J, et al. Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice. The Journal of clinical investigation. 2020;130(5):2391–2407. doi:10.1172/JCI127502

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Although gene-environment interactions have been implicated in the etiology of several disorders, the impact of paternal and/or maternal metabolic syndrome on the clinical phenotypes of offspring and the underlying genetic and epigenetic contributors of NAFLD have not been fully explored. To this end, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique nondietary model manifesting 3 hallmarks that confer high risk for the development of NAFLD: hyperglycemia, insulin resistance, and dyslipidemia. We report that parental metabolic syndrome epigenetically reprograms members of the TGF-β family, including neuronal regeneration-related protein (NREP) and growth differentiation factor 15 (GDF15). NREP and GDF15 modulate the expression of several genes involved in the regulation of hepatic lipid metabolism. In particular, NREP downregulation increases the protein abundance of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and ATP-citrate lyase (ACLY) in a TGF-β receptor/PI3K/protein kinase B-dependent manner, to regulate hepatic acetyl-CoA and cholesterol synthesis. Reduced hepatic expression of NREP in patients with NAFLD and substantial correlations between low serum NREP levels and the presence of steatosis and nonalcoholic steatohepatitis highlight the clinical translational relevance of our findings in the context of recent preclinical trials implicating ACLY in NAFLD progression.

Gupta MK, Vethe H, Softic S, Rao TN, Wagh V, Shirakawa J, Barsnes H, Vaudel M, Takatani T, Kahraman S, et al. Leptin Receptor Signaling Regulates Protein Synthesis Pathways and Neuronal Differentiation in Pluripotent Stem Cells. Stem cell reports. 2020;15(5):1067–1079. doi:10.1016/j.stemcr.2020.10.001

The role of leptin receptor (OB-R) signaling in linking pluripotency with growth and development and the consequences of dysfunctional leptin signaling on progression of metabolic disease is poorly understood. Using a global unbiased proteomics approach we report that embryonic fibroblasts (MEFs) carrying the db/db mutation exhibit metabolic abnormalities, while their reprogrammed induced pluripotent stem cells (iPSCs) show altered expression of proteins involved in embryonic development. An upregulation in expression of eukaryotic translation initiation factor 4e (Eif4e) and Stat3 binding to the Eif4e promoter was supported by enhanced protein synthesis in mutant iPSCs. Directed differentiation of db/db iPSCs toward the neuronal lineage showed defects. Gene editing to correct the point mutation in db/db iPSCs using CRISPR-Cas9, restored expression of neuronal markers and protein synthesis while reversing the metabolic defects. These data imply a direct role for OB-R in regulating metabolism in embryonic fibroblasts and key developmental pathways in iPSCs.

Kim H, Kulkarni RN. Epigenetics in β-cell adaptation and type 2 diabetes. Current opinion in pharmacology. 2020;55:125–131. doi:10.1016/j.coph.2020.10.008

Healthy pancreatic β-cells adapt to systemic insulin resistance to maintain normal blood glucose levels, and a failure of this adaptation leads to type 2 diabetes in humans. While genome-wide association studies have uncovered genetic variants that are associated with type 2 diabetes, it is still insufficient to explain the high prevalence of this disease. Epigenetics is the study of gene expression changes that do not involve DNA sequence alterations such as DNA methylation, histone modification, and non-coding RNAs. Over the last decade, a large number of studies have reported on the role of epigenetics in β-cell biology. In this review, we summarize the epigenetic mechanisms in β-cell adaptation and type 2 diabetes, including alterations in three-dimensional chromatin structure and RNA modifications.

2019