Association between multimorbidity and undiagnosed obstructive sleep apnea severity and their impact on quality of life in men over 40 years old.

BACKGROUND: Multimorbidity is common but little is known about its relationship with obstructive sleep apnea (OSA). METHODS: Men Androgen Inflammation Lifestyle Environment and Stress Study participants underwent polysomnography. Chronic diseases (CDs) were determined by biomedical measurement (diabetes, dyslipidaemia, hypertension, obesity), or self-report (depression, asthma, cardiovascular disease, arthritis). Associations between CD count, multimorbidity, apnea-hyponea index (AHI) and OSA severity and quality-of-life (QoL; mental & physical component scores), were determined using multinomial regression analyses, after adjustment for age. RESULTS: Of the 743 men participating in the study, overall 58% had multimorbidity (2+ CDs), and 52% had OSA (11% severe). About 70% of those with multimorbidity had undiagnosed OSA. Multimorbidity was associated with AHI and undiagnosed OSA. Elevated CD count was associated with higher AHI value and increased OSA severity. CONCLUSION: We demonstrate an independent association between the presence of OSA and multimorbidity in this representative sample of community-based men. This effect was strongest in men with moderate to severe OSA and three or more CDs, and appeared to produce a greater reduction in QoL when both conditions were present together.

The role of neuropeptide W in energy homeostasis.

Neuropeptide W is the endogenous ligand for G-protein-coupled receptors GPR7 and GPR8. In this review, we summarize findings on the distribution of neuropeptide W and its receptors in the central nervous system and the periphery, and discuss the role of NPW in food intake and energy homeostasis.

Men's help-seeking in the first year after diagnosis of localised prostate cancer.

This study describes sources of support utilised by men with localised prostate cancer in the first year after diagnosis and examines characteristics associated with help-seeking for men with unmet needs. A cross-sectional survey of 331 patients from a population-based sample who were in the first year after diagnosis (M = 9.6, SD = 1.9) was conducted to assess sources of support, unmet supportive care needs, domain-specific quality of life and psychological distress. Overall, 82% of men reported unmet supportive care needs. The top five needs were sexuality (58%); prostate cancer-specific (57%); psychological (47%); physical and daily living (41%); and health system and information (31%). Professional support was most often sought from doctors (51%). Across most domains, men who were older (Ps ≤ 0.03), less well educated (Ps ≤ 0.04) and more depressed (Ps ≤ 0.05) were less likely to seek help for unmet needs. Greater sexual help-seeking was related to better sexual function (P = 0.03), higher education (P ≤ 0.03) and less depression (P = 0.05). Unmet supportive care needs are highly prevalent after localised prostate cancer diagnosis with older age, lower education and higher depression apparent barriers to help-seeking. Interventions that link across medicine, nursing and community based peer support may be an accessible approach to meeting these needs. Clinical Trial Registry: Trial Registration: ACTRN12611000392965.

An open-label, phase 2, single centre, randomized, crossover design bioequivalence study of AndroForte 5 testosterone cream and Testogel 1% testosterone gel in hypogonadal men: study LP101.

We compared a novel 5% testosterone (T) cream (AndroForte 5, Lawley Pharmaceuticals, Australia) with a 1% T gel (Testogel, Besins Healthcare, Australia). Using an open-label crossover design, subjects were randomized to one of two treatment sequences using either the T gel or T cream first in a 1 : 1 ratio. Each treatment period was 30 days with a 7-14 days washout period between them. On Days 1 and 30 of each treatment period blood was sampled at -15, -5 min, 0, 2, 4, 5, 6, 7, 8, 9, 10, 12 and 16 h post study drug administration. Sixteen men with established androgen deficiency aged between 29 and 73 years, who had undertaken a washout from prior testosterone therapy participated in the study. One subject failed to complete both arms and another was excluded post-completion because of a major protocol violation. Bioequivalence was established based on key pharmacokinetic (PK) variables: AUC, C(avg), C(max), T(max), % fluctuation (with and without baseline correction) for the two formulations of testosterone on Day 1 and Day 30. The ratio and 90% CI of AUC 0.99 (0.86-1.14), C(max) 1.02 (0.84-1.24) and C(avg) 0.99 (0.86-1.14) for T cream/T gel were within the predetermined bio-equivalence criteria of 80% to 125% at Day 30. There were no statistically significant differences between secondary biochemical markers: serum dihydrotestosterone (DHT), oestradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH) and (FSH). The two testosterone formulations were shown to be bioequivalent.

Age-specific population centiles for androgen status in men.

AIM: The age-specific population profiles in men of circulating testosterone and its two bioactive metabolites dihydrotestosterone (DHT) and estradiol (E2) across the adult lifespan and its determinants are not well described. OBJECTIVE: Our objective was to deduce smoothed age-specific centiles of circulating testosterone, DHT, and E2 in men using pooled data from population-based studies in three Australian cities from liquid chromatography-mass spectrometry steroid measurements in a single laboratory. DESIGN, SETTING, AND PARTICIPANTS: We pooled data of 10 904 serum samples (serum testosterone, DHT, E2, age, height, and weight) from observational population-based studies in three major cities across Australia. MAIN OUTCOME MEASURES: Age-specific smoothed centiles for serum testosterone, DHT, and E2 in men aged 35-100 years were deduced by large sample data analysis methods. RESULTS: We found that serum testosterone, DHT, and E2 decline gradually from ages 35 onwards with a more marked decline after 80 years of age. Higher weight, BMI, and body surface area as well as shorter stature are associated with reduced serum testosterone, DHT, and E2. CONCLUSIONS: Among Australian men, there is a gradual progressive population-wide decline in androgen status during male aging until the age of 80 years after which there is a more marked decline. Obesity and short stature are associated with reduced androgen status. Research into the age-related decline in androgen status should focus on the progressive accumulation of age-related comorbidities to better inform optimal clinical trial design.

Panic disorder and incident coronary heart disease: a systematic review and meta-regression in 1131612 persons and 58111 cardiac events.

BACKGROUND: Substantial healthcare resources are devoted to panic disorder (PD) and coronary heart disease (CHD); however, the association between these conditions remains controversial. Our objective was to conduct a systematic review of studies assessing the association between PD, related syndromes, and incident CHD. METHOD: Relevant studies were retrieved from Medline, EMBASE, SCOPUS and PsycINFO without restrictions from inception to January 2015 supplemented with hand-searching. We included studies that reported hazard ratios (HR) or sufficient data to calculate the risk ratio and 95% confidence interval (CI) which were pooled using a random-effects model. Studies utilizing self-reported CHD were ineligible. Twelve studies were included comprising 1 131 612 persons and 58 111 incident CHD cases. RESULTS: PD was associated with the primary incident CHD endpoint [adjusted HR (aHR) 1.47, 95% CI 1.24-1.74, p < 0.00001] even after excluding angina (aHR 1.49, 95% CI 1.22-1.81, p < 0.00001). High to moderate quality evidence suggested an association with incident major adverse cardiac events (MACE; aHR 1.40, 95% CI 1.16-1.69, p = 0.0004) and myocardial infarction (aHR 1.36, 95% CI 1.12-1.66, p = 0.002). The risk for CHD was significant after excluding depression (aHR 1.64, 95% CI 1.45-1.85) and after depression adjustment (aHR 1.38, 95% CI 1.03-1.87). Age, sex, length of follow-up, socioeconomic status and diabetes were sources of heterogeneity in the primary endpoint. CONCLUSIONS: Meta-analysis showed that PD was independently associated with incident CHD, myocardial infarction and MACE; however, reverse causality cannot be ruled out and there was evidence of heterogeneity.

Serum sex steroids and steroidogenesis-related enzyme expression in skeletal muscle during experimental weight gain in men.

OBJECTIVES: Low-circulating testosterone is associated with development of type 2 diabetes in obese men. In this study, we examined the effects of experimental overfeeding and weight gain on serum levels of sex hormones and skeletal muscle expression of steroidogenic enzymes in healthy men with (FH+) and without (FH-) a family history of type 2 diabetes. METHODS: Following a 3-day lead in energy balanced diet, FH+ (n = 9) and FH- men (n = 11) were overfed by 5200 kJ/day (45% fat) for 28 days. Body weight, fasting glucose, insulin, sex steroid, sex hormone binding globulin (SHBG) levels, insulin sensitivity (hyperinsulinaemic-euglycaemic clamp) and body fat (DXA) were assessed in all individuals at baseline and day 28, and sex steroidogenesis-related enzyme expression in vastus lateralis biopsies was examined in a subset (n = 11). RESULTS: Body weight, fat mass and fasting insulin levels were increased by overfeeding (P < 0.01) and insulin was increased significantly more in FH+ men (P<0.01). Serum sex hormone binding globulin (SHBG) and 5α-dihydrotestosterone (DHT) were reduced with overfeeding (P < 0.05), and serum testosterone and DHT were reduced to a greater extent in FH+ men (P < 0.05). Overfeeding reduced mRNA expression of 3ß-hydroxysteroid dehydrogenase (HSD) and 17ßHSD (P ≤ 0.007), independently of group. 5α-Reductase (SRD5A1) mRNA expression was not changed overall, but a time by group interaction was observed (P = 0.04). CONCLUSION: Overfeeding reduced SHBG and muscle expression of enzymes involved in the formation of testosterone in skeletal muscle. Men with a family history of T2DM were more susceptible to deleterious outcomes of overfeeding with greater reductions in serum testosterone and DHT and greater increases in markers of insulin resistance, which may contribute to increased risk of developing type 2 diabetes.

Altered gastric vagal mechanosensitivity in diet-induced obesity persists on return to normal chow and is accompanied by increased food intake.

BACKGROUND AND AIMS: Gastric vagal afferents convey satiety signals in response to mechanical stimuli. The sensitivity of these afferents is decreased in diet-induced obesity. Leptin, secreted from gastric epithelial cells, potentiates the response of vagal afferents to mechanical stimuli in lean mice, but has an inhibitory effect in high-fat diet (HFD)-induced obese mice. We sought to determine whether changes in vagal afferent function and response to leptin in obesity were reversible by returning obese mice consuming a HFD to standard laboratory chow diet (SLD). METHODS: Eight-week-old female C57BL/6 mice were either fed a SLD (N=20) or HFD (N=20) for 24 weeks. A third group was fed a HFD for 12 weeks and then a SLD for a further 12 weeks (RFD, N=18). An in vitro gastro-oesophageal vagal afferent preparation was used to determine the mechanosensitivity of gastric vagal afferents and the modulatory effect of leptin (0.1-10 nM) was examined. Retrograde tracing and quantitative RT-PCR were used to determine the expression of leptin receptor (LepR) messenger RNA (mRNA) in whole nodose and specific cell bodies traced from the stomach. RESULTS: After 24 weeks, both the HFD and RFD mice had increased body weight, gonadal fat mass, plasma leptin, plasma insulin and daily energy consumption compared with the SLD mice. The HFD and RFD mice had reduced tension receptor mechanosensitivity and leptin further inhibited responses to tension in HFD, RFD but not SLD mice. Mucosal receptors from both the SLD and RFD mice were potentiated by leptin, an effect not seen in HFD mice. LepR expression was unchanged in the whole nodose, but was reduced in the mucosal afferents of the HFD and RFD mice. CONCLUSION: Disruption of gastric vagal afferent function by HFD-induced obesity is only partially reversible by dietary change, which provides a potential mechanism preventing maintenance of weight loss.

Modulation of murine gastric vagal afferent mechanosensitivity by neuropeptide W.

AIM: Neuropeptide W (NPW) is an endogenous ligand for the receptors GPR7 and GPR8 and is involved in central regulation of energy homeostasis. NPW in the periphery is found in gastric gastrin (G) cells. In the stomach, energy intake is influenced by vagal afferent signals, so we aimed to determine the effect of NPW on mechanosensitive gastric vagal afferents under different feeding conditions. METHODS: Female C57BL/6 mice (N > 10 per group) were fed a standard laboratory diet (SLD), high-fat diet (HFD) or were food restricted. The relationship between NPW immunopositive cells and gastric vagal afferent endings was determined by anterograde tracing and NPW immunohistochemistry. An in vitro gastro-oesophageal preparation was used to determine the functional effects of NPW on gastric vagal afferents. Expression of NPW in the gastric mucosa and GPR7 in whole nodose ganglia was determined by quantitative RT-PCR (QRT-PCR). The expression of GPR7 in gastric vagal afferent neurones was determined by retrograde tracing and QRT-PCR. RESULTS: Neuropeptide W immunoreactive cells were found in close proximity to traced vagal afferents. NPW selectively inhibited responses of gastric vagal tension receptors to stretch in SLD but not HFD or fasted mice. In the nodose ganglia, GPR7 mRNA was specifically expressed in gastric vagal afferent neurones. In fasted mice gastric mucosal NPW and nodose GPR7, mRNA was reduced compared with SLD. A HFD had no effect on gastric NPW mRNA, but down-regulated nodose GPR7 expression. CONCLUSION: Neuropeptide W modulates gastric vagal afferent activity, but the effect is dynamic and related to feeding status.

Sex hormone binding globulin, but not testosterone, is associated with the metabolic syndrome in overweight and obese women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and an increased risk of Type 2 diabetes and cardiovascular disease. Decreased SHBG and elevated testosterone are associated with metabolic syndrome and glucose intolerance in women. AIM: The aim of this study was to assess the relationship between SHBG and testosterone and metabolic syndrome and glucose intolerance in PCOS. MATERIAL/SUBJECTS AND METHODS: Cross-sectional study in overweight and obese premenopausal non-diabetic women with PCOS (no.=178: no.=55 metabolic syndrome, no.=16 glucose intolerance). Data were analyzed by multiple regression with metabolic syndrome, oral glucose tolerance test (OGTT) glucose or SHBG as dependent variables and reproductive hormones, insulin resistance, glucose tolerance, lipids or C-reactive protein as independent variables. RESULTS: Metabolic syndrome was independently associated with body mass index [odds ratio (OR) 1.084 95% confidence interval (CI) 1.034-1.170, p=0.015] and SHBG (OR 0.961 95% CI 0.932-0.995, p=0.018). Glucose tolerance was independently associated with OGTT insulin (ß=0.418, p<0.001), age (ß=0.154, p=0.033) and PRL (ß=-0.210, p=0.002). SHBG was independently associated with OGTT insulin (ß=-0.216, p=0.014) and PCOS diagnostic criteria (ß=0.197, p=0.010). CONCLUSIONS: SHBG, but not testosterone, is independently associated with metabolic syndrome in overweight women with PCOS and is associated with insulin resistance and PCOS diagnostic criteria.

Obesity and atrial fibrillation.

Atrial fibrillation (AF) is an increasing public health problem, often described as the epidemic of the new millennium. The rising health economic impact of AF, its association with poor quality of life and independent probability of increased mortality, has recently been highlighted. Although population ageing is regarded as an important contributor to this epidemic, obesity and its associated cardiometabolic comorbidities may represent the principal driving factor behind the current and projected AF epidemic. Obesity-related risk factors, such as hypertension, vascular disease, obstructive sleep apnea and pericardial fat, are thought to result in atrial electro-structural dysfunction. In addition, insulin resistance, its associated abnormalities in nutrient utilization and intermediary metabolic by-products are associated with structural and functional abnormalities, ultimately promoting AF. Recent elucidation of molecular pathways, including those responsible for atrial fibrosis, have provided mechanistic insights and the potential for targeted pharmacotherapy. In this article, we review the evidence for an obesity-related atrial electromechanical dysfunction, the mechanisms behind this and its impact on AF therapeutic outcomes. In light of the recently described mechanisms, we illustrate proposed management approaches and avenues for further investigations.

Prevalence and predictors of complementary and alternative medicine (CAM) use by men in Australian cancer outpatient services.

BACKGROUND: Although studies have shown that complementary and alternative medicine (CAM) use is common in cancer patients, no survey has assessed CAM use in men with a variety of cancers. In Australia, no data exist about male cancer patients' use of CAM. PATIENTS AND METHODS: A self-administered questionnaire was completed by 403 men attending four cancer outpatient services in Metropolitan Adelaide. Data were analyzed using Pearson's χ(2) tests and multivariate logistic regression analysis. RESULTS: CAMs were currently used by 52.9%, or used at some point by 61.5%, of respondents. The most popular CAM treatments were dietary supplements (36.1%), prayer (25.9%), herbs and botanicals (21.4%), and relaxation techniques/meditation (15.2%). CAM use was directed by a cancer specialist in 9.9% of respondents. Independent predictors of CAM use were metastatic cancer (P = 0.022), actively practicing religion (P = 0.008), and tertiary education (P = 0.007). CONCLUSIONS: CAM use in males is equally common across all cancer diagnoses, namely prostate, hematological malignancies, colorectal, lung, and other cancers. Oncologists should be aware that one-third of male patients modify their diet and/or search for spiritual guidance, particularly when diagnosed with metastatic cancer.

Insulin-stimulated glucose uptake and pathways regulating energy metabolism in skeletal muscle cells: the effects of subcutaneous and visceral fat, and long-chain saturated, n-3 and n-6 polyunsaturated fatty acids.

AIMS: The study aims to determine the effect of long-chain saturated and polyunsaturated (PUFA) fatty acids, specifically palmitic acid (PA; 16:0), docosahexaenoic acid (DHA; 22:6n-3) and linoleic acid (LA; 18:2n-6), and their interactions with factors from adipose tissue, on insulin sensitivity and lipid metabolism in skeletal muscle. METHODS: L6 myotubes were cultured with PA, DHA or LA (0.4mmol/l), with or without conditioned media from human subcutaneous (SC) and visceral (IAB) fat. Insulin-stimulated glucose uptake, lipid content, mRNA expression of key genes involved in nutrient utilization and protein expression of inhibitor protein inhibitor kappa B (IκB)-α and mammalian target of rapamycin (mTOR) were measured. RESULTS: PA and IAB fat reduced insulin-stimulated glucose uptake and their combined effect was similar to that of PA alone. PA-induced insulin resistance was ameliorated by inhibiting the de novo synthesis of ceramide, IκBα degradation or mTOR activation. The PA effect was also partially reversed by DHA and completely by LA in the presence of SC fat. PA increased diacylglycerol content, which was reduced by LA and to a greater extent when either IAB or SC fat was also present. PA increased SCD1 whereas DHA and LA increased AMPKα2 mRNA. In the presence of SC or IAB fat, the combination of PA with either DHA or LA decreased SCD1 and increased AMPKα2 mRNA. CONCLUSIONS: PA-induced insulin resistance in skeletal muscle involves inflammatory (nuclear factor kappa B/mTOR) and nutrient (ceramide) pathways. PUFAs promote pathways, at a transcriptional level, that increase fat oxidation and synergize with factors from SC fat to abrogate PA-induced insulin resistance.

Effects of a low-energy diet on sexual function and lower urinary tract symptoms in obese men.

OBJECTIVE: Abdominal obesity and type 2 diabetes mellitus are associated with erectile and urinary dysfunction in men. The extent to which sexual function and lower urinary tract symptoms (LUTSs) are improved by weight loss remains unclear. SUBJECTS: We compared the effects of 8 weeks of a low-calorie diet using meal replacements (Kicstart) on insulin sensitivity, plasma testosterone levels, erectile function (measured by the five-item version of the International Index of Erectile Function, IIEF-5), sexual desire (measured by the Sexual Desire Inventory, SDI) and LUTS (measured by the International Prostate Symptom Score, IPSS), in abdominally obese (body mass index >or=30 kg m(-2), waist circumference (WC) >or=102 cm) men (mean age 49.7 years) with uncomplicated diet or oral hypoglycemic-treated type 2 diabetes mellitus (n = 19) or without type 2 diabetes mellitus (n=25), with a control group of nondiabetic men (n = 26) with similar body mass index and WC. RESULTS: Weight loss of ∼ 10% was significantly associated with increased insulin sensitivity, plasma testosterone levels, IIEF-5 and SDI scores, as well as reduced WC and IPSS scores, in diabetic as well as nondiabetic men. The degree of weight loss was significantly associated with improvements in plasma testosterone levels (r = -0.34), erectile function (r = -0.26) and LUTS (r=0.65). Reduction in LUTS was significantly associated with increased plasma testosterone (r = -0.35), erectile function (r = -0.42) and sexual desire (r = -0.40). CONCLUSIONS: Diet-induced weight loss significantly and rapidly improves sexual function, and reduces LUTS, in obese middle-aged men with or without diabetes.

Obesity and testicular function.

Obesity in men, particularly when central, is associated with lower total testosterone [TT], free testosterone [FT] and sex hormone-binding globulin [SHBG], and a greater decline in TT and FT with increasing age compared with lean men. Obesity-related conditions such as obstructive sleep apnea, insulin resistance and type 2 diabetes mellitus are independently associated with decreased plasma testosterone. Possible mechanisms include decreased LH pulse amplitude, inhibitory effects of oestrogen at the hypothalamus and pituitary and the effects of leptin and other peptides centrally and on Leydig cells. Obese men have reduced sperm concentration and total sperm count compared to lean men but sperm motility and morphology appear unaffected. The cause and effect relationships between low plasma androgen levels, obesity and the metabolic syndrome, and associated cardiometabolic risk remain unclear. While weight loss normalizes TT and FT in obese men, androgen replacement in the short term does not significantly improve cardiometabolic risk profile despite reducing fat mass.

Chronic disease trends due to excess body weight in Australia.

Trends in chronic diseases provide insights into strategies required to improve population health. The authors determined prevalence and multiple-adjusted population attributable risk (PAR) estimates of chronic diseases because of lifestyle factors among Australian adults between 1989-90 and 2004-5, accounting for demographic factors. Between 1989-90 and 2004-5, prevalence increased for diabetes (3.8-6.0%, P < 0.001) and high cholesterol (11.3-13.9%, P < 0.001), but decreased for high blood pressure (21.4-20.4%, P = 0.003) and cardiovascular disease (CVD, 6.2-5.4%, P < 0.001). Prevalence increased for body mass index (BMI) 25-29.9 (30.3-34.9%, P < 0.001), BMI 30-34.9 (7.4-13.5%, P < 0.001) and BMI 35+ (2.1-5.4%, P < 0.001), but decreased for metabolic equivalent-hours per week (MET-hr/week) 0 (36.8-33.1%, P < 0.001) and current smokers (27.6-24.4%, P < 0.001). Diabetes, high cholesterol and high blood pressure burden increased mostly for 60+ years, lowest income quintiles and high BMI (30-34.9 and 35+). Diabetes and CVD burden increased mostly for MET-hr/week 0. Many chronic disease cases would have been theoretically prevented if adults had no prior exposure to BMI 25-29.9 (PAR 9-17%), BMI 30+ (PAR 1-14%) and MET-hr/week 0 (PAR 6-14%). Reducing exposure to lifestyle hazards across the lifespan is required for reversing the rising burden of chronic diseases. Decreases in CVD and high blood pressure prevalence were likely due to targeted improvements in health care, indicating that more can and should be done.

Maternal overnutrition suppresses the phosphorylation of 5'-AMP-activated protein kinase in liver, but not skeletal muscle, in the fetal and neonatal sheep.

Epidemiological studies have shown that infants exposed to an increased supply of nutrients before birth are at increased risk of type 2 diabetes in later life. We have investigated the hypothesis that fetal overnutrition results in reduced expression and phosphorylation of the cellular fuel sensor, AMP-activated kinase (AMPK) in liver and skeletal muscle before and after birth. From 115 days gestation, ewes were fed either at or approximately 55% above maintenance energy requirements. Postmortem was performed on lamb fetuses at 139-141 days gestation (n = 14) and lambs at 30 days of postnatal age (n = 21), and liver and quadriceps muscle were collected at each time point. The expression of AMPKalpha1 and AMPKalpha2 mRNA was determined by quantitative RT-PCR (qRT-PCR). The abundance of AMPKalpha and phospho-AMPKalpha (P-AMPKalpha) was determined by Western blot analysis, and the proportion of the total AMPKalpha pool that was phosphorylated in each sample (%P-AMPKalpha) was determined. The ratio of AMPKalpha2 to AMPKalpha1 mRNA expression was lower in fetuses compared with lambs in both liver and muscle, independent of maternal nutrition. Hepatic %P-AMPKalpha was lower in both fetuses and lambs in the Overfed group and %P-AMPKalpha in the lamb liver was inversely related to plasma glucose concentrations in the first 24 h after birth (r = 0.73, P < 0.025). There was no effect of maternal overnutrition on total AMPKalpha or P-AMPKalpha abundance in liver or skeletal muscle. We have, therefore, demonstrated that AMPKalpha responds to signals of increased nutrient availability in the fetal liver. Suppression of hepatic AMPK phosphorylation may contribute to increased glucose production, and basal hyperglycemia, present in lambs of overfed ewes in early postnatal life.

AMPK and ACC phosphorylation: effect of leptin, muscle fibre type and obesity.

Leptin stimulates fatty acid oxidation via the phosphorylation of AMPK (AMP-activated protein kinase) and ACC (acetyl-CoA carboxylase). Obesity is associated with resistance to the effects of leptin. We determined the action of leptin on AMPKalpha and ACCbeta phosphorylation and lipid metabolism in soleus (SOL) and extensor digitorum longus (EDL) muscles from lean and obese Wistar rats after 1 and 100 nM leptin. Both leptin doses stimulated phosphorylation of AMPKalpha and ACCbeta (P

Effects of cannabinoid receptors on skeletal muscle oxidative pathways.

The endocannabinoids, a recently discovered endogenous, lipid derived, signaling system regulating energy metabolism, have effects on central and peripheral energy metabolism predominantly via the cannabinoid receptor type 1 (CB1). CB1 is expressed centrally in the hypothalamus and nucleus accumbens and peripherally in adipocytes and skeletal muscle. This study determined the effect of endocannabinoids on the expression of genes regulating energy metabolism in human skeletal muscle. Primary cultures of myotubes (lean and obese; n=3/group) were treated with the cannabinoid receptor agonist, anandamide (AEA) (0.2 and 5microM) and the CB1 specific antagonist AM251 (0.2 and 5microM) separately and in combination for 24h. The expression of mRNA for AMP-activated protein kinase (AMPK) alpha 1 (alpha1) and alpha 2 (alpha2), pyruvate dehydrogenase kinase 4 (PDK4) and peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) were determined using 'Real Time' RT-PCR. AMPKalpha1 mRNA increased in lean and obese myotubes in response to AM251 (P<0.05). AEA inhibited the effect of AM251 on AMPKalpha1 mRNA levels in myotubes from lean and obese subjects (P<0.05); the dose-response curve was shifted to the left in the obese. In response to AM251, irrespective of the presence of AEA, PDK4 expression was decreased in lean and obese myotubes (P<0.05). Taken together these data suggest that endocannabinoids regulate pathways affecting skeletal muscle oxidation, effects particularly evident in myotubes from obese individuals.

Relative androgen deficiency in relation to obesity and metabolic status in older men.

BACKGROUND: Although androgen deficiency in men has been linked with obesity and the metabolic syndrome, whether it predisposes to, or is a consequence of, type 2 diabetes mellitus (T2DM) is still unclear. OBJECTIVE: To determine the relationship between plasma androgen levels, obesity, metabolic status and T2DM in men of 70 years or older. DESIGN AND METHODS: A sample of 195 men from the Australian Longitudinal Study of Ageing with a mean age of 76.2 +/- 0.3 years were followed up for 8 years. Total testosterone (TT), fasting plasma glucose (FPG), urate, serum creatinine, total cholesterol (TC), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TG), blood pressure (BP), body mass index (BMI), waist circumference (WC) and diabetic status were assessed at baseline. Self-reported diabetic status was obtained after 8 years. Metabolic syndrome was diagnosed based on the Third National Cholesterol Education Program Adult Treatment Panel clinical criteria. RESULTS: TT levels were lower in diabetic men compared with non-diabetic men (12.1 +/- 0.7 vs. 14.2 +/- 0.4 nmol/l, p = 0.026). TT levels in healthy, non-diabetic men over 80 years of age were lower (11.9 +/- 0.8 vs. 15.0 +/- 0.5 nmol/l, p = 0.002) than TT levels in those aged 70-79 years, inversely related to BMI (r = -0.26, p = 0.001), WC (r = -0.30, p < 0.001) and TG (r = -0.22, p = 0.005) and positively related to LDL-C (r = 0.25, p = 0.002). Men with the metabolic syndrome had significantly lower levels of TT and HDL-C, and higher values of BP, FPG, TG, BMI and WC, compared with those without. However, no significant difference in plasma TT levels was noted between men with incident T2Dm and healthy men. Stepwise linear regression analysis revealed that only LDL-C and WC related significantly to the variance of TT. Multiple logistic regression revealed FPG to be the only independent predictor of incident diabetes (odds ratio = 60.2, p = 0.003). CONCLUSIONS: Testosterone levels continue to decline even in healthy men over the age of 80 years. Although TT levels were inversely related to visceral obesity and several components of the metabolic syndrome, our data do not support a predictive or causative role for decreasing TT levels in the development of incident T2Dm. Androgen deficiency is consequent upon, rather than a cause of, poor metabolic status.