Decreased IGF1R attenuates senescence and improves function in pancreatic ß-cells.

Introduction: The enhanced ß-cell senescence that accompanies insulin resistance and aging contributes to cellular dysfunction and loss of transcriptional identity leading to type 2 diabetes (T2D). While senescence is among the 12 recognized hallmarks of aging, its relation to other hallmarks including altered nutrient sensing (insulin/IGF1 pathway) in ß-cells is not fully understood. We previously reported that an increased expression of IGF1R in mouse and human ß-cells is a marker of older ß-cells; however, its contribution to age-related dysfunction and cellular senescence remains to be determined. Methods: In this study, we explored the direct role of IGF1R in ß-cell function and senescence using two independent mouse models with decreased IGF1/IGF1R signaling: a) Ames Dwarf mice (Dwarf +/+), which lack growth hormone and therefore have reduced circulating levels of IGF1, and b) inducible ß-cell-specific IGF1R knockdown (ßIgf1rKD) mice. Results: Compared to Dwarf+/- mice, Dwarf+/+ mice had lower body and pancreas weight, lower circulating IGF1 and insulin levels, and lower IGF1R and p21Cip1 protein expression in ß-cells, suggesting the suppression of senescence. Adult ßIgf1rKD mice showed improved glucose clearance and glucose-induced insulin secretion, accompanied by decreased p21Cip1 protein expression in ß-cells. RNA-Seq of islets isolated from these ßIgf1rKD mice revealed the restoration of three signaling pathways known to be downregulated by aging: sulfide oxidation, autophagy, and mTOR signaling. Additionally, deletion of IGF1R in mouse ß-cells increased transcription of genes important for maintaining ß-cell identity and function, such as Mafa, Nkx6.1, and Kcnj11, while decreasing senescence-related genes, such as Cdkn2a, Il1b, and Serpine 1. Decreased senescence and improved insulin-secretory function of ß-cells were also evident when the ßIgf1rKD mice were fed a high-fat diet (HFD; 60% kcal from fat, for 5 weeks). Discussion: These results suggest that IGF1R signaling plays a causal role in aging-induced ß-cell dysfunction. Our data also demonstrate a relationship between decreased IGF1R signaling and suppressed cellular senescence in pancreatic ß-cells. Future studies can further our understanding of the interaction between senescence and aging, developing interventions that restore ß-cell function and identity, therefore preventing the progression to T2D.

Bromodomain Inhibition Reveals FGF15/19 As a Target of Epigenetic Regulation and Metabolic Control.

Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we investigated epigenetic control of systemic metabolism by bromodomain-containing proteins (Brds), which are transcriptional regulators binding to acetylated histone, in both intestinal cells and mice treated with the bromodomain inhibitor JQ-1. In vivo treatment with JQ-1 resulted in hyperglycemia and severe glucose intolerance. Whole-body or tissue-specific insulin sensitivity was not altered by JQ-1; however, JQ-1 treatment reduced insulin secretion during both in vivo glucose tolerance testing and ex vivo incubation of isolated islets. JQ-1 also inhibited expression of fibroblast growth factor (FGF) 15 in the ileum and decreased FGF receptor 4-related signaling in the liver. These adverse metabolic effects of Brd4 inhibition were fully reversed by in vivo overexpression of FGF19, with normalization of hyperglycemia. At a cellular level, we demonstrate Brd4 binds to the promoter region of FGF19 in human intestinal cells; Brd inhibition by JQ-1 reduces FGF19 promoter binding and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum and FGF signaling in the liver and a contributor to the gut-liver axis and systemic glucose metabolism.

Effects of exercise on cellular and tissue aging.

The natural aging process is carried out by a progressive loss of homeostasis leading to a functional decline in cells and tissues. The accumulation of these changes stem from a multifactorial process on which both external (environmental and social) and internal (genetic and biological) risk factors contribute to the development of adult chronic diseases, including type 2 diabetes mellitus (T2D). Strategies that can slow cellular aging include changes in diet, lifestyle and drugs that modulate intracellular signaling. Exercise is a promising lifestyle intervention that has shown antiaging effects by extending lifespan and healthspan through decreasing the nine hallmarks of aging and age-associated inflammation. Herein, we review the effects of exercise to attenuate aging from a clinical to a cellular level, listing its effects upon various tissues and systems as well as its capacity to reverse many of the hallmarks of aging. Additionally, we suggest AMPK as a central regulator of the cellular effects of exercise due to its integrative effects in different tissues. These concepts are especially relevant in the setting of T2D, where cellular aging is accelerated and exercise can counteract these effects through the reviewed antiaging mechanisms.

Unique Human and Mouse ß-Cell Senescence-Associated Secretory Phenotype (SASP) Reveal Conserved Signaling Pathways and Heterogeneous Factors.

The aging of pancreatic ß-cells may undermine their ability to compensate for insulin resistance, leading to the development of type 2 diabetes (T2D). Aging ß-cells acquire markers of cellular senescence and develop a senescence-associated secretory phenotype (SASP) that can lead to senescence and dysfunction of neighboring cells through paracrine actions, contributing to ß-cell failure. In this study, we defined the ß-cell SASP signature based on unbiased proteomic analysis of conditioned media of cells obtained from mouse and human senescent ß-cells and a chemically induced mouse model of DNA damage capable of inducing SASP. These experiments revealed that the ß-cell SASP is enriched for factors associated with inflammation, cellular stress response, and extracellular matrix remodeling across species. Multiple SASP factors were transcriptionally upregulated in models of ß-cell senescence, aging, insulin resistance, and T2D. Single-cell transcriptomic analysis of islets from an in vivo mouse model of reversible insulin resistance indicated unique and partly reversible changes in ß-cell subpopulations associated with senescence. Collectively, these results demonstrate the unique secretory profile of senescent ß-cells and its potential implication in health and disease.

Effects of Y1 receptor agonist on the pancreatic islet of diet-induced obese and diabetic mice.

AIMS: Agonists of the NPY receptor might be potential in protecting pancreatic islets from injury. We aimed to characterize the role of [Leu31, Pro34]-PYY, an NPYR1 agonist, in pancreatic islets of a diet-induced obesity and insulin resistance model. METHODS: We studied long-term high-fat diet intake as a model and selective agonist of the Y1 receptor to explore the pancreatic islet architecture and stereology, and insulin secretion in isolated islets and a whole animal model. Gene and protein expressions were assessed in isolated islets investigating the signaling cascades involved in inflammation, insulin signaling, and secretion. Also, the insulin release potential was studied in vitro. RESULTS: Our data reveal that an infusion of NPYR1 for 14 days did not change the body mass of mice and eating behavior. NPYR1 did not modify the islet and beta-cell mass but positively impacted the inflammatory process by lowering the expressions of Tnf alpha and If gamma. Besides, NPYR1 restored the insulin signaling and the exocytose pattern by activating the PDX1/STAT3 pathway and improving the leptin signaling cascade. CONCLUSIONS: The findings are compellingly indicating the potential effect of the NPYR1 as a target for improving the insulin resistance condition. As such, the infusion of the NPYR1 agonist would help to enhance insulin secretion by the beta-cell from the PDX1/STAT3 pathway and the improvement of the inflammatory process.

Sex-linked changes and high cardiovascular risk markers in the mature progeny of father, mother, or both father and mother consuming a high-fructose diet.

OBJECTIVES: The aim of this study was to observe the developmental origins of health and disease affecting offspring owing to the consumption of a diet containing high fructose by the father or mother or both, considering that progeny only received a control diet during postnatal life. METHODS: Male (future father) and female (future mother) C57 BL/6 mice were fed a high-fructose diet (HFru; 45% energy) or a control diet (C) for 8 wk before mating until lactation. The offspring was termed according to sex, maternal diet (first acrostic), and paternal diet (second acrostic); and received a balanced control diet until 3-mo of age when they were sacrificed. Body mass (BM), plasmatic leptin, adiponectin, uric acid, and systolic blood pressure (BP) were measured in mature offspring. RESULTS: Fasting glycemia and insulin were elevated in HFru fathers and mothers. Although there was no change in BM, fasting glycemia, or insulin of the offspring, those of HFru fathers, HFru mothers, and HFru fathers and mothers presented higher genital fat pad, leptin, uric acid, and BP, and lower adiponectin. The values of leptin and BP were maximized when both parents consumed a HFru diet. Also, there was sexual dimorphism in most of the variables, with the male offspring being affected to a greater extent than the females. CONCLUSIONS: Consumption of a fructose-rich diet by the father, the mother, or both negatively affected the adipokines, BP, and uric acid concentrations of mature offspring, with males being more affected than females. It is significant to consider that high BP and plasmatic uric acid correspond to markers of elevated cardiovascular risk in the progeny.

Obese fathers lead to an altered metabolism and obesity in their children in adulthood: review of experimental and human studies / Pais obesos levam a metabolismo alterado e obesidade em seus filhos na idade adulta: revisão de estudos experimentais e humanos

Abstract Objective: To discuss the recent literature on paternal obesity, focusing on the possible mechanisms of transmission of the phenotypes from the father to the children. Sources: A non-systematic review in the PubMed database found few publications in which paternal obesity was implicated in the adverse transmission of characteristics to offspring. Specific articles on epigenetics were also evaluated. As the subject is recent and still controversial, all articles were considered regardless of year of publication. Summary of findings: Studies in humans and animals have established that paternal obesity impairs their hormones, metabolism, and sperm function, which can be transmitted to their offspring. In humans, paternal obesity results in insulin resistance/type 2 diabetes and increased levels of cortisol in umbilical cord blood, which increases the risk factors for cardiovascular disease. Notably, there is an association between body fat in parents and the prevalence of obesity in their daughters. In animals, paternal obesity led to offspring alterations on glucose-insulin homeostasis, hepatic lipogenesis, hypothalamus/feeding behavior, kidney of the offspring; it also impairs the reproductive potential of male offspring with sperm oxidative stress and mitochondrial dysfunction. An explanation for these observations (human and animal) is epigenetics, considered the primary tool for the transmission of phenotypes from the father to offspring, such as DNA methylation, histone modifications, and non-coding RNA. Conclusions: Paternal obesity can induce programmed phenotypes in offspring through epigenetics. Therefore, it can be considered a public health problem, affecting the children's future life.

Resumo Objetivo: Discutir a literatura recente sobre obesidade paterna, focalizando os possíveis mecanismos de transmissão dos fenótipos do pai para os filhos. Fontes: Uma revisão não-sistemática no banco de dados PubMed encontrou poucas publicações com obesidade paterna implicada com a transmissão adversa das características à prole. Artigos específicos sobre epigenética também foram avaliados. Como o assunto é recente e ainda controverso, todos os trabalhos foram considerados independentemente do ano de publicação. Resumo dos achados: Estudos em seres humanos e animais estabeleceram que a obesidade do pai prejudica seus hormônios, metabolismo e função espermática, que pode ser transmitida à prole. Em humanos, a obesidade paterna resulta em resistência à insulina / diabetes tipo 2 e aumento do nível de cortisol no sangue do cordão umbilical, que aumenta os fatores de risco para doença cardiovascular. Notavelmente, existe associação entre a gordura corporal nos pais e a prevalência de obesidade em suas filhas. Em animais, pais obesos condicionam, na prole, a homeostase glicose-insulina, lipogênese hepática, hipotálamo / comportamento alimentar, rim, prejudicam o potencial reprodutivo da prole masculina com estresse oxidativo espermático e disfunção mitocondrial. Uma explicação para estas observações (humanos e animais) é a epigenética, considerada a ferramenta básica para a transmissão de fenótipos do pai à prole, como a metilação do DNA, modificações nas histonas, e RNA não codificante. Conclusões: A obesidade paterna pode induzir fenótipos programados na prole através da epigenética. Portanto, a obesidade paterna pode ser considerada um problema de saúde pública, afetando a vida futura das crianças.

Obese fathers lead to an altered metabolism and obesity in their children in adulthood: review of experimental and human studies.

OBJECTIVE: To discuss the recent literature on paternal obesity, focusing on the possible mechanisms of transmission of the phenotypes from the father to the children. SOURCES: A non-systematic review in the PubMed database found few publications in which paternal obesity was implicated in the adverse transmission of characteristics to offspring. Specific articles on epigenetics were also evaluated. As the subject is recent and still controversial, all articles were considered regardless of year of publication. SUMMARY OF FINDINGS: Studies in humans and animals have established that paternal obesity impairs their hormones, metabolism, and sperm function, which can be transmitted to their offspring. In humans, paternal obesity results in insulin resistance/type 2 diabetes and increased levels of cortisol in umbilical cord blood, which increases the risk factors for cardiovascular disease. Notably, there is an association between body fat in parents and the prevalence of obesity in their daughters. In animals, paternal obesity led to offspring alterations on glucose-insulin homeostasis, hepatic lipogenesis, hypothalamus/feeding behavior, kidney of the offspring; it also impairs the reproductive potential of male offspring with sperm oxidative stress and mitochondrial dysfunction. An explanation for these observations (human and animal) is epigenetics, considered the primary tool for the transmission of phenotypes from the father to offspring, such as DNA methylation, histone modifications, and non-coding RNA. CONCLUSIONS: Paternal obesity can induce programmed phenotypes in offspring through epigenetics. Therefore, it can be considered a public health problem, affecting the children's future life.