Type 2 diabetes has become a pervasive public health problem. The etiology of the disease has not been fully defined but appears to involve abnormalities in peripheral and central nervous system pathways, as well as prominent inflammatory components. Because nicotinic acetylcholine receptors (nAChRs) are known to interact with anti-inflammatory pathways and have been implicated in control of appetite and body weight, as well as lipid and energy metabolism, we examined their role in modulating biological parameters associated with the disease. In a model of type 2 diabetes, the homozygous leptin-resistant db/db obese mouse, we measured the effects of a novel ␣7 nAChR-selective agonist [5-methyl-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide (TC-7020)] on body mass, glucose and lipid metabolism, and proinflammatory cytokines. Oral administration of TC-7020 reduced weight gain and food intake, reduced elevated glucose and glycated hemoglobin levels, and lowered elevated plasma levels of triglycerides and the proinflammatory cytokine tumor necrosis factor-␣. These changes were reversed by the ␣7-selective antagonist methyllycaconitine, confirming the involvement of ␣7 nAChRs. Prevention of weight gain, decreased food intake, and normalization of glucose levels were also blocked by the Janus kinase 2 (JAK2) inhibitor ␣-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG-490), suggesting that these effects involve linkage of ␣7 nAChRs to the JAK2-signal transducer and activator of transcription 3 signaling pathway. The results show that ␣7 nAChRs play a central role in regulating biological parameters associated with diabetes and support the potential of targeting these receptors as a new therapeutic strategy for treatment.In 2000 it was reported that at least 171 million people worldwide (2.8% of the population) suffered from diabetes, and it has been estimated that the incidence will almost double by the year 2030 (Wild et al., 2004). The Centers for Disease Control and Prevention has designated the disease an epidemic. Specific pathogenic entities contributing to diabetic risk, such as central adiposity, ectopic fat accumulation, hyperlipidemia, and inflammation, have been well characterized. In general, diabetes is believed to be secondary to an insulin-resistant state, which is associated with excess adiposity (Sykiotis and Papavassiliou, 2001). Insulin resistance in skeletal muscle, liver, and adipose tissue impedes glucose uptake and results in the release of free fatty acids and the characteristically associated dyslipidemia. Elevations in postprandial blood glucose levels and ultimately in fasting glucose levels result in compensatory hyperinsulinemia, a condition that is initially accompanied by islet ␤-cell hypertrophy and eventual failure (Sykiotis and Papavassiliou, 2001).A key factor that underlies the development of diabetes is a characteristic systemic inflammation, marked by increases in the venous blood concentrations of C-reactive protein, interleukin 6 (IL-6), and tum...

Rationale: Obesity is a risk factor for cardiovascular dysfunction, yet the underlying factors driving this impaired function remain poorly understood. Insulin resistance is a common pathology in obese patients and has been shown to impair vascular function. Whether insulin resistance or obesity, itself, is causal remains unclear. Objective: The present study tested the hypothesis that insulin resistance is the underlying mediator for impaired NO-mediated dilation in obesity by genetic deletion of the insulin-desensitizing enzyme protein tyrosine phosphatase (PTP)1B in db/db mice. Methods and Results: The db/db mouse is morbidly obese, insulin-resistant, and has tissue-specific elevation in PTP1B expression compared to lean controls. In db/db mice, PTP1B deletion improved glucose clearance, dyslipidemia, and insulin receptor signaling in muscle and fat. Hepatic insulin signaling in db/db mice was not improved by deletion of PTP1B, indicating specific amelioration of peripheral insulin resistance. Additionally, obese mice demonstrate an impaired endothelium dependent and independent vasodilation to acetylcholine and sodium nitroprusside, respectively. This impairment, which correlated with increased superoxide in the db/db mice, was corrected by superoxide scavenging. Increased superoxide production was associated with increased expression of NAD(P)H oxidase 1 and its molecular regulators, Noxo1 and Noxa1. Conclusions: Deletion of PTP1B improved both endothelium dependent and independent NO-mediated dilation and reduced superoxide generation in db/db mice. PTP1B deletion did not affect any vascular function in lean mice. Taken T he prevalence of obesity and its cardiovascular complications represents a significant health concern in Western societies, 1,2 but the root causes of cardiovascular dysfunction in obese individuals remain unclear. Metabolic dysfunction, notably insulin resistance, is evident in obesity. 3,4 It has been speculated that insulin resistance, rather than other aspects of obesity, is the underlying cause of cardiovascular injury in obese patients. [5][6][7][8][9] This hypothesis has been difficult to test because insulin-sensitizing drugs have off-target effects 4,10 and nonobese models of insulin resistance do not evaluate the relative importance of obesity versus insulin resistance. [11][12][13][14][15][16][17] The insulin receptor is a classic receptor tyrosine kinase 18 and, as such, is deactivated by protein tyrosine phosphatases, notably protein tyrosine phosphatase (PTP)1B. 19 -21 Deletion of PTP1B improves insulin sensitivity in mouse models of obesity, 22 and putative PTP1B antagonists have been used pharmacologically to improve glucose tolerance. [23][24][25] Increases in the activity and/or expression of PTP1B correlate with blunted insulin signaling in a variety of tissue types. 26 -28 Whether PTP1B deletion and amelioration of insulin resistance improves cardiovascular dysfunction associated with obesity remains unknown.The present study tested the hypothesis that PTP1B deleti...

BackgroundA sedentary lifestyle is an independent risk factor for cardiovascular disease and exercise has been shown to ameliorate this risk. Inactivity is associated with a loss of muscle mass, which is also reversed with isometric exercise training. The relationship between muscle mass and vascular function is poorly defined. The aims of the current study were to determine whether increasing muscle mass by genetic deletion of myostatin, a negative regulator of muscle growth, can influence vascular function in mesenteric arteries from obese db/db mice.Methods and ResultsMyostatin expression was elevated in skeletal muscle of obese mice and associated with reduced muscle mass (30% to 50%). Myostatin deletion increased muscle mass in lean (40% to 60%) and obese (80% to 115%) mice through increased muscle fiber size (P<0.05). Myostatin deletion decreased adipose tissue in lean mice, but not obese mice. Markers of insulin resistance and glucose tolerance were improved in obese myostatin knockout mice. Obese mice demonstrated an impaired endothelial vasodilation, compared to lean mice. This impairment was improved by superoxide dismutase mimic Tempol. Deletion of myostatin improved endothelial vasodilation in mesenteric arteries in obese, but not in lean, mice. This improvement was blunted by nitric oxide (NO) synthase inhibitor l‐NG‐nitroarginine methyl ester (l‐NAME). Prostacyclin (PGI2)‐ and endothelium‐derived hyperpolarizing factor (EDHF)‐mediated vasodilation were preserved in obese mice and unaffected by myostatin deletion. Reactive oxygen species) was elevated in the mesenteric endothelium of obese mice and down‐regulated by deletion of myostatin in obese mice. Impaired vasodilation in obese mice was improved by NADPH oxidase inhibitor (GKT136901). Treatment with sepiapterin, which increases levels of tetrahydrobiopterin, improved vasodilation in obese mice, an improvement blocked by l‐NAME.ConclusionsIncreasing muscle mass by genetic deletion of myostatin improves NO‐, but not PGI2‐ or EDHF‐mediated vasodilation in obese mice; this vasodilation improvement is mediated by down‐regulation of superoxide.

Insulin resistance in tissues such as muscle and fat is an underlying cause of obesity‐induced vascular dysfunction. Myostatin, secreted by skeletal muscle, has been associated with muscle metabolism and lowering myostatin may improve insulin sensitivity.HypothesisIncreasing muscle mass via myostatin deletion in obesity improves whole‐body metabolism and vascular function. A dual knockout (KO) approach was used including dual heterozygous lean mice, lean myostatin KO, db/db and db/db mice with and without myostatin KO. Myostatin KO increased gastrocnemius and gluteal muscle mass (37–52% in lean mice, 83% in obese mice). Myostatin KO improved HbA1c (6.33±0.50 vs. 10.00±1.54) in db/db mice, and fasting glucose in both lean and db/db mice, while myostatin KO had no effect on lipid metabolism. Glucose tolerance test results showed that db/db mice were insulin resistant and that myostatin KO improved insulin sensitivity in db/db mice. Obese db/db mice demonstrated an impaired microvascular vasodilation to acetylcholine that was improved by KO of myostatin. Adrenergic constriction was similar in all groups. Improvement of vasodilator capacity by myostatin KO was not attributed to vascular sensitivity to nitric oxide or changes in vascular structure and mechanics. Taken together, these data suggested that myostatin deletion in obese mice improved insulin resistance and endothelium dependent vasodilation.