Ins1-Cre and Ins1-CreER Gene Replacement Alleles Are Susceptible To Silencing By DNA Hypermethylation.

Targeted gene ablation studies of the endocrine pancreas have long suffered from suboptimal Cre deleter strains. In many cases, Cre lines purportedly specific for beta cells also displayed expression in other islet endocrine cells or in a subset of neurons in the brain. Several pancreas and endocrine Cre lines have experienced silencing or mosaicism over time.

Deletion of Nrf2 shortens lifespan in C57BL6/J male mice but does not alter the health and survival benefits of caloric restriction.

Caloric restriction (CR) is the leading non-pharmaceutical dietary intervention to improve health- and lifespan in most model organisms. A wide array of cellular pathways is induced in response to CR and CR-mimetics, including the transcriptional activator Nuclear factor erythroid-2-related factor 2 (Nrf2), which is essential in the upregulation of multiple stress-responsive and mitochondrial enzymes. Nrf2 is necessary in tumor protection but is not essential for the lifespan extending properties of CR in outbred mice.

Toll-like receptors TLR2 and TLR4 block the replication of pancreatic β cells in diet-induced obesity.

Consumption of a high-energy Western diet triggers mild adaptive β cell proliferation to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. In the present study we show that the toll-like receptors TLR2 and TLR4 inhibited the diet-induced replication of β cells in mice and humans. The combined, but not the individual, loss of TLR2 and TLR4 increased the replication of β cells, but not that of α cells, leading to enlarged β cell area and hyperinsulinemia in diet-induced obesity.

Benefits of Caloric Restriction in Longevity and Chemical-Induced Tumorigenesis Are Transmitted Independent of NQO1.

Caloric restriction (CR) is the most potent nonpharmacological intervention known to both protect against carcinogenesis and delay aging in laboratory animals. There is a growing number of anticarcinogens and CR mimetics that activate NAD(P)H:quinone oxidoreductase 1 (NQO1). We have previously shown that NQO1, an antioxidant enzyme that acts as an energy sensor through modulation of intracellular redox and metabolic state, is upregulated by CR.

Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.

The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA.

Conserved and species-specific molecular denominators in mammalian skeletal muscle aging.

Aging is a complex phenomenon involving functional decline in multiple physiological systems. We undertook a comparative analysis of skeletal muscle from four different species, i.e.

Opposing effects of prostaglandin E receptors EP3 and EP4 on mouse and human β-cell survival and proliferation.

Objective: Hyperglycemia and systemic inflammation, hallmarks of Type 2 Diabetes (T2D), can induce the production of the inflammatory signaling molecule Prostaglandin E (PGE) in islets. The effects of PGE are mediated by its four receptors, E-Prostanoid Receptors 1-4 (EP1-4). EP3 and EP4 play opposing roles in many cell types due to signaling through different G proteins, G and G, respectively.

Regulation of pancreatic β-cell function and mass dynamics by prostaglandin signaling.

Prostaglandins (PGs) are signaling lipids derived from arachidonic acid (AA), which is metabolized by cyclooxygenase (COX)-1 or 2 and class-specific synthases to generate PGD, PGE, PGF, PGI (prostacyclin), and thromboxane A. PGs signal through G-protein coupled receptors (GPCRs) and are important modulators of an array of physiological functions, including systemic inflammation and insulin secretion from pancreatic islets. The role of PGs in β-cell function has been an active area of interest, beginning in the 1970s.

Unexpected effects of the MIP-CreER transgene and tamoxifen on β-cell growth in C57Bl6/J male mice.

Transgenic mouse models have been fundamental in the discovery of factors that regulate β-cell development, mass, and function. Several groups have recently shown that some of these models display previously uncharacterized phenotypes due to the transgenic system itself. These include impaired islet function and increased β-cell mass due to the presence of a human growth hormone (hGH) minigene as well as impaired β-cell proliferation in response to tamoxifen (TM) administration.

Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival.

The regulation of pancreatic β cell mass is a critical factor to help maintain normoglycemia during insulin resistance. Nutrient-sensing G protein-coupled receptors (GPCR) contribute to aspects of β cell function, including regulation of β cell mass. Nutrients such as free fatty acids (FFAs) contribute to precise regulation of β cell mass by signaling through cognate GPCRs, and considerable evidence suggests that circulating FFAs promote β cell expansion by direct and indirect mechanisms.

The PGE2 EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice.

Mice carrying a targeted disruption of the prostaglandin E2 (PGE2) E-prostanoid receptor 3 (EP3) gene, Ptger3, were fed a high-fat diet (HFD), or a micronutrient matched control diet, to investigate the effects of disrupted PGE2-EP3 signaling on diabetes in a setting of diet-induced obesity. Although no differences in body weight were seen in mice fed the control diet, when fed a HFD, EP3(-/-) mice gained more weight relative to EP3(+/+) mice. Overall, EP3(-/-) mice had increased epididymal fat mass and adipocyte size; paradoxically, a relative decrease in both epididymal fat pad mass and adipocyte size was observed in the heaviest EP3(-/-) mice.

High-fat diet-induced β-cell proliferation occurs prior to insulin resistance in C57Bl/6J male mice.

Both short- (1 wk) and long-term (2-12 mo) high-fat diet (HFD) studies reveal enhanced β-cell mass due to increased β-cell proliferation. β-Cell proliferation following HFD has been postulated to occur in response to insulin resistance; however, whether HFD can induce β-cell proliferation independent of insulin resistance has been controversial. To examine the kinetics of HFD-induced β-cell proliferation and its correlation with insulin resistance, we placed 8-wk-old male C57Bl/6J mice on HFD for different lengths of time and assayed the following: glucose tolerance, insulin secretion in response to glucose, insulin tolerance, β-cell mass, and β-cell proliferation.

Of mice and men: the benefits of caloric restriction, exercise, and mimetics.

During aging there is an increasing imbalance of energy intake and expenditure resulting in obesity, frailty, and metabolic disorders. For decades, research has shown that caloric restriction (CR) and exercise can postpone detrimental aspects of aging. These two interventions invoke a similar physiological signature involving pathways associated with stress responses and mitochondrial homeostasis.