cyclin-d1 and Glucose-Intolerance

Diabetes and metabolic perturbation are global health challenges. Sleep insufficiency may trigger metabolic dysregulation leading to diabetes. However, the intergenerational transmission of this environmental information is not clearly understood. The research objective was to determine the possible effect of paternal sleep deprivation on the metabolic phenotype of the offspring and to investigate the underlying mechanism of epigenetic inheritance. Male offspring of sleep-deprived fathers exhibit glucose intolerance, insulin resistance, and impaired insulin secretion. In these SD-F1 offspring, a reduction in beta cell mass and proliferation of beta cells were observed. Mechanistically, in pancreatic islets of SD-F1 offspring, we identified alterations in DNA methylation at the promoter region of the LRP5 (LDL receptor related protein 5) gene, a coreceptor of Wnt signaling, resulting in downregulation of downstream effectors cyclin D1, cyclin D2, and Ctnnb1. Restoration of Lrp5 in the pancreas of SD-F1 male mice could improve impaired glucose tolerance and expression of cyclin D1, cyclin D2, and Ctnnb1. This study might significantly contribute to our understanding of the effects of sleeplessness on health and metabolic disease risk from the perspective of the heritable epigenome.

Topics: Animals; Cyclin D1; Cyclin D2; Diabetes Mellitus; DNA Methylation; Fathers; Glucose Intolerance; Humans; Islets of Langerhans; Low Density Lipoprotein Receptor-Related Protein-5; Male; Melatonin; Mice; Sleep Deprivation

Childhood obesity is associated with renal diseases. Maternal obesity is a risk factor linked to increased adipocytokines and metabolic disorders in the offspring. Therefore, we studied the impact of maternal obesity on renal-intrinsic insulin and adipocytokine signaling and on renal function and structure. To induce maternal obesity, female mice were fed a high-fat diet (HFD) or a standard diet (SD; control group) prior to mating, during gestation, and throughout lactation. A third group of dams was fed HFD only during lactation (HFD-Lac). After weaning at postnatal day (P)21, offspring of all groups received SD. Clinically, HFD offspring were overweight and insulin resistant at P21. Although no metabolic changes were detected at P70, renal sodium excretion was reduced by 40%, and renal matrix deposition increased in the HFD group. Mechanistically, two stages were differentiated. In the early stage (P21), compared with the control group, HFD showed threefold increased white adipose tissue, impaired glucose tolerance, hyperleptinemia, and hyperinsulinemia. Renal leptin/Stat3-signaling was activated. In contrast, the Akt/ AMPKα cascade and Krüppel-like factor 15 expression were decreased. In the late stage (P70), although no metabolic differences were detected in HFD when compared with the control group, leptin/Stat3-signaling was reduced, and Akt/AMPKα was activated in the kidneys. This effect was linked to an increase of proliferative (cyclinD1/D2) and profibrotic (ctgf/collagen IIIα1) markers, similar to leptin-deficient mice. HFD-Lac mice exhibited metabolic changes at P21 similar to HFD, but no other persistent changes. This study shows a link between maternal obesity and metabolic programming of renal structure and function and intrinsic-renal Stat3/Akt/AMPKα signaling in the offspring.

Topics: Adipokines; Adipose Tissue, White; AMP-Activated Protein Kinases; Animals; Collagen Type III; Connective Tissue Growth Factor; Cyclin D1; Cyclin D2; Diet, High-Fat; DNA-Binding Proteins; Female; Glucose Intolerance; Insulin; Insulin Resistance; Kidney; Kruppel-Like Transcription Factors; Leptin; Male; Mice; Obesity; Overweight; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins c-akt; Signal Transduction; Sodium; STAT3 Transcription Factor; Transcription Factors

Expanding β-cell mass through β-cell proliferation is considered a potential therapeutic approach to treat β-cell failure in diabetic patients. A necessary step toward achieving this goal is to identify signaling pathways that regulate β-cell proliferation in vivo. Here we show that osteocalcin, a bone-derived hormone, regulates β-cell replication in a cyclin D1-dependent manner by signaling through the Gprc6a receptor expressed in these cells. Accordingly, mice lacking Gprc6a in the β-cell lineage only are glucose intolerant due to an impaired ability to produce insulin. Remarkably, this regulation occurs during both the perinatal peak of β-cell proliferation and in adulthood. Hence, the loss of osteocalcin/Gprc6a signaling has a profound effect on β-cell mass accrual during late pancreas morphogenesis. This study extends the endocrine role of osteocalcin to the developmental period and establishes osteocalcin/Gprc6a signaling as a major regulator of β-cell endowment that can become a potential target for β-cell proliferative therapies.

Topics: Aging; Animals; Cell Lineage; Cell Proliferation; Cells, Cultured; Cyclin D1; Glucose Intolerance; Insulin; Insulin-Secreting Cells; Mice; Mice, Inbred C57BL; Osteocalcin; Receptors, G-Protein-Coupled; Signal Transduction

Regulation of adult beta-cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G(1) phase of the cell cycle. Here we show that cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2(-/-) or cyclin D1(+/-) D2(-/-) mice. However, beta-cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2(-/-) mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1(+/-) mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1(-/+) D2(-/-) mice as beta-cell mass decreased after birth. Thus, cyclins D2 and D1 were essential for beta-cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in beta cells could prevent or cure diabetes.

Topics: Animals; Blood Glucose; Cell Proliferation; Cyclin D1; Cyclin D2; Cyclins; Diabetes Mellitus; Gene Expression; Glucagon; Glucose Intolerance; Insulin; Islets of Langerhans; Male; Mice; Mice, Knockout