Sirtuin 1 and sirtuin 3: physiological modulators of metabolism.

The sirtuins are a family of highly conserved NAD(+)-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD(+) levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.

International Consensus Statement on Obstructive Sleep Apnea.

BACKGROUND: Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). METHODS: Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. RESULTS: The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. CONCLUSION: This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

A new glucagon and GLP-1 co-agonist eliminates obesity in rodents.

We report the efficacy of a new peptide with agonism at the glucagon and GLP-1 receptors that has potent, sustained satiation-inducing and lipolytic effects. Selective chemical modification to glucagon resulted in a loss of specificity, with minimal change to inherent activity. The structural basis for the co-agonism appears to be a combination of local positional interactions and a change in secondary structure. Two co-agonist peptides differing from each other only in their level of glucagon receptor agonism were studied in rodent obesity models. Administration of PEGylated peptides once per week normalized adiposity and glucose tolerance in diet-induced obese mice. Reduction of body weight was achieved by a loss of body fat resulting from decreased food intake and increased energy expenditure. These preclinical studies indicate that when full GLP-1 agonism is augmented with an appropriate degree of glucagon receptor activation, body fat reduction can be substantially enhanced without any overt adverse effects.

Metabolic benefits from Sirt1 and Sirt1 activators.

PURPOSE OF REVIEW: To evaluate the role of mammalian Sirt1 and Sirt1 activators in the protection from metabolic disorders such as diet-induced obesity, diabetes type 2, or nonalcoholic fatty liver disease. RECENT FINDINGS: Sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases that are activated by NAD+ and inhibited by NAD in its reduced form (NADH). Sirtuins act as cellular energy sensors that deacetylate numerous proteins involved in energy and glucose homeostasis, which in turn induce a wide range of physiological changes that counteract detrimental effects of metabolic stressors. SUMMARY: Sirt1 targets numerous proteins, including peroxisome proliferator-activated receptor (PPAR)-gamma, PPAR-gamma coactivator (PGC)-1alpha, uncoupling protein 2 (UCP2), and nuclear factor-kappa B, which play key roles in various metabolic disorders. This review summarizes these key targets of Sirt1 and the physiological relevance of those interactions. Also, new results on Sirt1-knockout and overexpressor mouse models are presented to substantiate metabolic benefits from Sirt1 activation. Finally, this review gives an overview on recent efforts to activate Sirt1 pharmacologically by using resveratrol or small-molecule Sirt1 activators with improved biopotency.

The HPA axis modulates the CNS melanocortin control of liver triacylglyceride metabolism.

The central melanocortin system regulates lipid metabolism in peripheral tissues such as white adipose tissue. Alterations in the activity of sympathetic nerves connecting hypothalamic cells expressing melanocortin 3/4 receptors (MC3/4R) with white adipocytes have been shown to partly mediate these effects. Interestingly, hypothalamic neurons producing corticotropin-releasing hormone and thyrotropin-releasing hormone co-express MC4R. Therefore we hypothesized that regulation of hypothalamo-pituitary adrenal (HPA) and hypothalamo-pituitary thyroid (HPT) axes activity by the central melanocortin system could contribute to its control of peripheral lipid metabolism. To test this hypothesis, we chronically infused rats intracerebroventricularly (i.c.v.) either with an MC3/4R antagonist (SHU9119), an MC3/4R agonist (MTII) or saline. Rats had been previously adrenalectomized (ADX) and supplemented daily with 1mg/kg corticosterone (s.c.), thyroidectomized (TDX) and supplemented daily with 10 µg/kgL-thyroxin (s.c.), or sham operated (SO). Blockade of MC3/4R signaling with SHU9119 increased food intake and body mass, irrespective of gland surgery. The increase in body mass was accompanied by higher epididymal white adipose tissue (eWAT) weight and higher mRNA content of lipogenic enzymes in eWAT. SHU9119 infusion increased triglyceride content in the liver of SO and TDX rats, but not in those of ADX rats. Concomitantly, mRNA expression of lipogenic enzymes in liver was increased in SO and TDX, but not in ADX rats. We conclude that the HPA and HPT axes do not play an essential role in mediating central melanocortinergic effects on white adipose tissue and liver lipid metabolism. However, while basal hepatic lipid metabolism does not depend on a functional HPA axis, the induction of hepatic lipogenesis due to central melanocortin system blockade does require a functional HPA axis.

Acylation type determines ghrelin's effects on energy homeostasis in rodents.

Ghrelin is a gastrointestinal polypeptide that acts through the ghrelin receptor (GHSR) to promote food intake and increase adiposity. Activation of GHSR requires the presence of a fatty-acid (FA) side chain on amino acid residue serine 3 of the ghrelin molecule. However, little is known about the role that the type of FA used for acylation plays in the biological action of ghrelin. We therefore evaluated a series of differentially acylated peptides to determine whether alterations in length or stability of the FA side chain have an impact on the ability of ghrelin to activate GHSR in vitro or to differentially alter food intake, body weight, and body composition in vivo. Fatty acids principally available in the diet (such as palmitate C16) and therefore representing potential substrates for the ghrelin-activating enzyme ghrelin O-acyltransferase (GOAT) were used for dose-, time-, and administration/route-dependent effects of ghrelin on food intake, body weight, and body composition in rats and mice. Our data demonstrate that altering the length of the FA side chain of ghrelin results in the differential activation of GHSR. Additionally, we found that acylation of ghrelin with a long-chain FA (C16) delays the acute central stimulation of food intake. Lastly, we found that, depending on acylation length, systemic and central chronic actions of ghrelin on adiposity can be enhanced or reduced. Together our data suggest that modification of the FA side-chain length can be a novel approach to modulate the efficacy of pharmacologically administered ghrelin.

Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling.

We studied interscapular brown adipose tissue (iBAT) activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R)-deficient mice after the administration of the proglucagon-derived peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduces body weight and increases iBAT thermogenesis. This was independent of changes in feeding and insulin responsiveness but correlated with increased activity of sympathetic fibers innervating brown adipose tissue (BAT). Despite being a GCG receptor agonist, OXM requires GLP-1R activation to induce iBAT thermogenesis. The increase in thermogenesis in WT mice correlates with increased expression of genes upregulated by adrenergic signaling and required for iBAT thermogenesis, including PGC1a and UCP-1. In spite of the increase in iBAT thermogenesis induced by GLP-1R activation in WT mice, Glp1r(-/-) mice exhibit a normal response to cold exposure, demonstrating that endogenous GLP-1R signaling is not essential for appropriate thermogenic response after cold exposure. Our data suggest that the increase in BAT thermogenesis may be an additional mechanism whereby pharmacological GLP-1R activation controls energy balance.

CNS opioid signaling separates cannabinoid receptor 1-mediated effects on body weight and mood-related behavior in mice.

Existing monotherapies for the treatment of obesity provide only modest weight loss and/or have adverse side effects, and this is also the case with the cannabinoid receptor 1 (CB1) inverse agonist, rimonabant. We aimed to investigate the possibility of improving efficacy and reducing side effects of rimonabant by cotreatment with opioid system antagonists. Using both genetic and pharmacological removal of opioid signaling in mice, we investigated changes in body weight, food intake, and fat mass as well as behavioral outcomes of interactions between opioid ligands and the CB1 using the inverse agonist, rimonabant. The ability of rimonabant to reduce weight is enhanced by removal of with µ-opioid receptor signaling, while not being greatly affected by κ-opioid receptor blockade. Additionally, lack of opioid signaling, especially κ-opioid receptor, attenuated the ability of rimonabant to decrease immobility time in the Porsolt forced-swim test, a preclinical model of depression. These results indicate that the endogenous opioid system is involved in modulating both the metabolic and mood effects of rimonabant.

Ghrelin, peptide YY and their hypothalamic targets differentially regulate spontaneous physical activity.

Recent studies suggest that spontaneous physical activity (SPA) may be under the non-conscious control of neuroendocrine circuits that are known to control food intake. To further elucidate endocrine gut-brain communication as a component of such circuitry, we here analyzed long-term and acute effects of the gastrointestinal hormones ghrelin and PYY 3-36 as well as their hypothalamic neuropeptide targets NPY, AgRP and POMC (alpha-MSH), on locomotor activity and home cage behaviors in rats. For the analysis of SPA, we used an automated infrared beam break activity measuring system, combined with a novel automated video-based behavior analysis system (HomeCageScan (HCS)). Chronic (one-month) peripheral infusion of ghrelin potently increased body weight and fat mass in rats. Such positive energy balance was intriguingly not due to an overall increased caloric ingestion, but was predominantly associated with a decrease in SPA. Chronic intracerebroventricular infusion (7 days) of ghrelin corroborated the decrease in SPA and suggested a centrally mediated mechanism. Central administration of AgRP and NPY increased food intake as expected. AgRP administration led to a delayed decrease in SPA, while NPY acutely (but transiently) increased SPA. Behavioral dissection using HCS corroborated the observed acute and transient increases of food intake and SPA by central NPY infusion. Acute central administration of alpha-MSH rapidly decreased food intake but did not change SPA. Central administration of the NPY receptor agonist PYY 3-36 transiently increased SPA. Our data suggest that the control of spontaneous physical activity by gut hormones or their neuropeptide targets may represent an important mechanistic component of energy balance regulation.

Action profile of the antiobesity drug candidate oleoyl-estrone in rats.

Oleoyl-estrone (OE) has been presented as a potential antiobesity therapeutic, but the published series of studies from one laboratory has not yet been independently confirmed, and the exact mechanism of action is unknown. Based on the hypothesis that OE has potential for the treatment of obesity, male and female rats were chronically treated with several doses of OE to evaluate the impact of this compound on energy metabolism. Body weight, body composition, energy balance parameters and the expression of hypothalamic neuropeptides regulating food intake as well as key markers of the reproductive system were examined. OE impressively reduced food consumption and body weight gain in both sexes. Although a major part of the loss in body weight could be explained by decreased fat mass, a substantial loss of lean mass also occurred after OE administration. The loss of weight can be sufficiently explained by the suppression of food consumption, as there were no major changes in energy expenditure, locomotor activity or respiratory quotient. In situ hybridization data showed no significant change in the expression of key neuropeptides and hormone receptors regulating feeding behavior after OE treatment. Cocaine-amphetamine-regulated transcript (CART) mRNA levels were decreased in the arcuate nucleus of OE-treated rats. Hypogonadism and low plasma testosterone levels were found in OE-treated males, whereas females showed substantially increased liver size. The present data suggest that OE decreases food intake and body weight but also appears to cause a significant impact on the hypothalamus-pituitary-reproductive axis.

Prevention of peritoneal adhesions with an in situ cross-linkable hyaluronan hydrogel delivering budesonide.

Peritoneal adhesions are tissue connections that form within the abdominopelvic cavity following surgery or other injuries. They can cause major medical complications. Barrier devices and pharmacological agents have been used to prevent adhesion formation, with mixed success. We hypothesize that an adhesion barrier which also delivers anti-adhesion drugs can address both physical and physiological causes for adhesion formation. Here, we describe an in situ cross-linking hyaluronan hydrogel (barrier device) containing the glucocorticoid receptor agonist budesonide. Budesonide was chosen because of the known role of inflammation in adhesion formation, hyaluronan because of its known biocompatibility in the peritoneum. The system, consisting of two cross-linkable precursor liquids, was applied using a double-barreled syringe, forming a flexible and durable hydrogel in less than 5 s. We applied this formulation or controls to the injured sites after the second injury in a severe repeat sidewall defect-cecum abrasion model of peritoneal adhesion formation in the rabbit. Large adhesions (median area 15.4 cm(2)) developed in all saline-treated animals. Adhesion formation and area were slightly mitigated in animals treated with budesonide in saline (median area 5.0 cm(2)) or the hydrogel without budesonide (median area 4.9 cm(2)). The incidence and area of adhesions were dramatically reduced in animals treated with budesonide in the hydrogel (median area 0.0 cm(2)). In subcutaneous injections in rats, budesonide in hydrogel reduced inflammation compared to hydrogel alone. In summary, budesonide in a hyaluronan hydrogel is easy to use and highly effective in preventing adhesions in our severe repeated injury model. It is a potentially promising system for post-surgical adhesion prevention, and suggests that the effectiveness of barrier devices can be greatly enhanced by concurrent drug delivery.