Transcription factor-based cellular reprogramming has opened the way to converting somatic cells to a pluripotent state, but has faced limitations resulting from the requirement for transcription factors and the relative inefficiency of the process. We show here that expression of the miR302/367 cluster rapidly and efficiently reprograms mouse and human somatic cells to an iPS state without a requirement for exogenous transcription factors. This miRNA-based reprogramming approach is two orders of magnitude more efficient than standard Oct4/Sox2/Klf4/Myc-mediated methods. Mouse and human miR302/367 iPS cells display similar characteristics to Oct4/Sox2/Klf4/Myc-iPS cells, including pluripotency marker expression, teratoma formation, and, for mouse cells, chimera contribution and germline contribution. We found that miR367 expression is required for miR302/367-mediated reprogramming and activates Oct4 gene expression, and that suppression of Hdac2 is also required. Thus, our data show that miRNA and Hdac-mediated pathways can co-operate in a powerful way to reprogram somatic cells to pluripotency.

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SUMMARY p53 is well known for its tumor suppressor role, but this protein also has a poorly understood role in the regulation of metabolism. Human studies have implicated a common polymorphism at codon 72 of p53 in diabetic and pre-diabetic phenotypes. To understand this role, we utilized a humanized mouse model of the p53 codon 72 variants and monitored these mice following challenge with a high fat diet (HFD). Mice with the arginine 72 (R72) variant of p53 developed more severe obesity and glucose intolerance on a HFD, compared to mice with the proline 72 variant (P72). R72 mice developed insulin resistance, islet hypertrophy, increased infiltration of immune cells, and fatty liver disease. Gene expression analyses and studies with small molecule inhibitors indicate that the p53 target genes Tnf and Npc1l1 underlie this phenotype. These results shed light on the role of p53 in obesity, metabolism and inflammation.

Objective To examine associations of molecular markers of brain insulin signaling with Alzheimer disease (AD) and cognition among older persons with or without diabetes. Methods This clinical–pathologic study was derived from a community‐based cohort study, the Religious Orders Study. We studied 150 individuals (mean age at death =87 years, 48% women): 75 with and 75 without diabetes (matched by sex on age at death and education). Using enzyme‐linked immunosorbent assay, immunohistochemistry, and ex vivo stimulation of brain tissue with insulin, we assessed insulin signaling in the postmortem middle frontal gyrus cortex. Postmortem data documented AD neuropathology. Clinical evaluations documented cognitive function proximate to death, based on 17 neuropsychological tests. In adjusted regression analyses, we examined associations of brain insulin signaling with diabetes, AD, and level of cognition. Results Brain insulin receptor substrate‐1 (IRS1) phosphorylation (pS307IRS1/total IRS1) and serine/threonine‐protein kinase (AKT) phosphorylation (pT308AKT1/total AKT1) were similar in persons with or without diabetes. AKT phosphorylation was associated with the global AD pathology score (p = 0.001). In contrast, IRS1 phosphorylation was not associated with AD (p = 0.536). No other associations of insulin signaling were found with the global AD score, including when using the ex vivo brain insulin stimulation method. In secondary analyses, normalized pT308AKT1 was positively correlated with both the amyloid burden and tau tangle density, and no other associations of brain insulin signaling with neuropathology were observed. Moreover, normalized pT308AKT1 was associated with a lower level of global cognitive function (estimate = −0.212, standard error = 0.097; p = 0.031). Interpretation Brain AKT phosphorylation, a critical node in the signaling of insulin and other growth factors, is associated with AD neuropathology and lower cognitive function. ANN NEUROL 2020;88:513–525

Rationale: Leptin treats upper airway obstruction and alveolar hypoventilation in leptin-deficient ob/ob mice. However, obese humans and mice with diet-induced obesity (DIO) are resistant to leptin because of poor permeability of the blood-brain barrier. We propose that intranasal leptin will bypass leptin resistance and treat sleep-disordered breathing in obesity. Objectives: To assess if intranasal leptin can treat obesity hypoventilation and upper airway obstruction during sleep in mice with DIO. Methods: Male C57BL/6J mice were fed with a high-fat diet for 16 weeks. A single dose of leptin (0.4 mg/kg) or BSA (vehicle) were administered intranasally or intraperitoneally, followed by either sleep studies (n = 10) or energy expenditure measurements (n = 10). A subset of mice was treated with leptin daily for 14 days for metabolic outcomes (n = 20). In a separate experiment, retrograde viral tracers were used to examine connections between leptin receptors and respiratory motoneurons. Measurements and Main Results: Acute intranasal, but not intraperitoneal, leptin decreased the number of oxygen desaturation events in REM sleep, and increased ventilation in non-REM and REM sleep, independently of metabolic effects. Chronic intranasal leptin decreased food intake and body weight, whereas intraperitoneal leptin had no effect. Intranasal leptin induced signal transducer and activator of transcription 3 phosphorylation in hypothalamic and medullary centers, whereas intraperitoneal leptin had no effect. Leptin receptor-positive cells were synaptically connected to respiratory motoneurons. Conclusions: In mice with DIO, intranasal leptin bypassed leptin resistance and significantly attenuated sleep-disordered breathing independently of body weight.

is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15R␣ take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15R␣ promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15R␣ on metabolism and obesity are currently unknown. We report that mice lacking IL-15R␣ (IL-15R␣ Ϫ/Ϫ ) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15R␣ Ϫ/Ϫ mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15R␣ Ϫ/Ϫ are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15R␣ in metabolism and obesity.interleukin-15 receptor alpha; diet-induced obesity; muscle; fatty acid oxidation; fatigue recovery; glucose homeostasis ACCUMULATION OF EXCESSIVE body fat is a physiological consequence of unnecessary caloric intake. With greater worldwide food production, often the caloric intake largely exceeds the physiological energy requirements, and as a result, the obesity pandemic is growing at alarming rates in both developed and developing countries (21,47). Apart from the role of environmental factors, particularly an energy-dense diet and sedentary lifestyle, obesity also has important genetic determinants that have been conserved across species. Identifying the molecular mechanisms regulating metabolic efficiency (the capacity to convert energy intake into storable energy forms) is of great interest because of the low success in using caloric restriction as a means to manage obesity. Indeed, a number of pathways have been recently identified that reduce the extent of dietinduced obesity (DIO) by decreasing metabolic efficiency rather than energy input (8,10,11,43,56,59,60). Targeting these pathways with pharmacological approaches may also have the advantage of reproducing some of the benefits normally associated with physical exercise. Together with caloric restriction, exercise is a mainstay of a healthy life style and contributes to the control of metabolic efficiency. In addition to converting energy into movement, exercise increases the rates of lipolysis and fat oxidation, promotes heat dissipation (49, 53), and causes long-term changes in the expression of numerous genes, including IL-15R␣/IL-15 (55).IL-15 and its primary binding partner IL-15R␣ have emerged as important regulators of cell functions in both lymphoid and nonlymphoid tissues. Their transcripts are detectable in a variety of tissues, including skeletal muscle, liver, or adipose (http://biogps.org/#gotoϭwelcome). Some of the proposed noncanonical roles of IL-15/IL-15R␣ signaling are mediating anabolic...

SummaryThe ability to generate pluripotent stem cells from a variety of cell and tissue sources through the ectopic expression of a specific set of transcription factors has revolutionized regenerative biology. The development of this reprogramming technology not only makes it possible to perform basic research on human stem cells that do not have to be derived from embryos, but also allows patient-specific cells and tissues to be generated for therapeutic use. Optimizing this process will probably lead to a better and more efficient means of generating pluripotent stem cells. Here, we discuss recent findings that show that, in addition to transcription factors, microRNAs can promote pluripotent reprogramming and can even substitute for these pluripotency transcription factors in some cases. Taking into consideration that microRNAs have the potential to be used as small-molecule therapeutics, such findings open new possibilities for both pluripotent stem cell reprogramming and the reprogramming of cells into other cell lineages.

Study Objectives Obesity leads to obstructive sleep apnea (OSA), which is recurrent upper airway obstruction during sleep, and obesity hypoventilation syndrome (OHS), hypoventilation during sleep resulting in daytime hypercapnia. Impaired leptin signaling in the brain was implicated in both conditions, but mechanisms are unknown. We have previously shown that leptin stimulates breathing and treats OSA and OHS in leptin- deficient ob/ob mice and leptin-resistant diet-induced obese mice and that leptin’s respiratory effects may occur in the dorsomedial hypothalamus (DMH). We hypothesized that leptin receptor LepR b–deficient db/db mice have obesity hypoventilation and that restoration of leptin signaling in the DMH will increase ventilation during sleep in these animals. Methods We measured arterial blood gas in unanesthetized awake db/db mice. We subsequently infected these animals with Ad-LepR  b or control Ad-mCherry virus into the DMH and measured ventilation during sleep as well as CO2 production after intracerebroventricular (ICV) infusions of phosphate-buffered saline or leptin. Results Awake db/db mice had elevated CO2 levels in the arterial blood. Ad-LepR  b infection resulted in LepR  b expression in the DMH neurons in a similar fashion to wildtype mice. In LepR  b-DMH db/db mice, ICV leptin shortened REM sleep and increased inspiratory flow, tidal volume and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2 production. Leptin had no effect on upper airway obstruction in these animals. Conclusion Leptin stimulates breathing and treats obesity hypoventilation acting on LepR b-positive neurons in the DMH.