High-fat diet-induced obesity ablates gastric vagal afferent circadian rhythms

Rats with high-fat diet (HFD)-induced obesity increase daytime eating, suggesting an alteration in circadian food intake mechanisms. Gastric vagal afferents (GVAs) respond to mechanical stimuli to initiate satiety. These signals are dampened in HFD mice and exhibit circadian variations inversely with food intake in lean mice. Furthermore, leptin shows circadian variation in its circulating level and is able to modulate GVA mechanosensitivity. However, whether leptin's ability to modulate GVAs occurs in a circadian manner is unknown. Therefore, we investigated whether changes in the circadian intake of food in HFD-induced obesity is associated with a disruption in GVA circadian rhythms. Eight-week-old male C57BL/6 mice were fed a standard laboratory diet (SLD) or a HFD for 12 weeks. A subgroup of SLD and HFD mice were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at zeitgeber time 0 (ZT0) and stomach content was measured. After 12 weeks, HFD mice consumed more food during the light phase through larger and more frequent meals compared with SLD mice. SLD mice exhibited circadian fluctuation in stomach content, which peaked at ZT18 and reached a nadir at ZT9. At these time points, both tension and mucosal receptor mechanosensitivity were the lowest and highest, respectively. HFD mice exhibited little circadian variation in stomach content or GVA mechanosensitivity. Leptin potentiated mucosal receptor mechanosensitivity only in SLD mice and with reduced potency during the dark phase. In conclusion, loss of circadian variation in GVA signaling may underpin changes in eating behavior in HFD-induced obesityStephen J. Kentish, Andrew D. Vincent, David J. Kennaway, Gary A. Wittert, and Amanda J. Pag

Identifying the internalizing disorder clusters among recently hospitalized cardiovascular disease patients: a receiver operating characteristics study

Depression and anxiety disorders are common among cardiovascular disease (CVD) populations, leading several cardiology societies to recommend routine screening to streamline psychological interventions. However, it remains poorly understood whether routine screening in CVD populations identifies the broader groups of disorders that cluster together within individuals, known as anxious-misery and fear. This study examines the screening utility of four anxiety and depression questionnaires to identify the two internalizing disorder clusters; anxious-misery and fear. Patients with a recent hospital admission for CVD (n = 85, 69.4% males) underwent a structured clinical interview with the MINI International Neuropsychiatric Interview. The participants also completed the Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder (GAD-7) scale, Overall Anxiety Severity Impairment Scale (OASIS), and the stress subscale of the Depression Anxiety Stress Scale (DASS). The PHQ-9 and the GAD-7 yielded appropriate screening properties to detect three different iterations of the anxious-misery cluster (sensitivity >80.95% and specificity >82.81%). The GAD-7 was the only instrument to display favorable screening properties to detect a fear cluster omitting post-traumatic stress disorder (PTSD) but including obsessive-compulsive disorder (OCD; sensitivity 81.25%, specificity 76.81%). These findings indicate that the PHQ-9 and GAD-7 could be implemented to reliably screen for anxious-misery disorders among CVD in-patients, however, the receiver operating characteristics (ROC) to detect fear disorders were contingent on the placement of PTSD and OCD within clusters. The findings are discussed in relation to routine screening guidelines in CVD populations and contemporary understandings of the internalizing disorders.Megan Grech, Deborah A. Turnbull, Gary A. Wittert, Phillip J. Tully and the CHAMPS Investigator

The effect of multimorbidity patterns and the impact of comorbid anxiety and depression on primary health service use: the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study

This study sought to determine patterns of multimorbidity and quantify their impact on use of primary health services in the presence and absence of anxiety and depression among a cohort of urban community-dwelling men in Australia. The analytic sample consisted of men (n = 2039; age 38-85) from the follow-up wave of a prospective cohort study of all participants of the Florey Adelaide Male Ageing Study (FAMAS; Stage 2 [2007-2010]) and age-matched men from the North-West Adelaide Health Study (NWAHS; Stage 3 [2008-2010]). Self-reported data and linkage with a national universal health coverage scheme (Medicare) provided information on the prevalence of eight chronic conditions and health service utilization information (including annual GP visits). Obesity and cardiovascular disease (CVD) were associated with the highest number of comorbid conditions. Two nonrandom multimorbidity "clusters" emerged: "CVD, Obesity, Diabetes" and "CVD, Obesity, Osteoarthritis." Participants with conditions comorbid with CVD were more likely to have 10 or more annual GP visits, compared to multimorbidity involving other conditions. In comparison to participants without CVD, the presence of CVD increased the chance of having 10 or more annual GP visits (adjusted risk ratio: 3.7; 95% CI [2.8, 4.8]). When CVD was comorbid with anxiety and depression, having 10 or more annual GP visits was more common (adjusted risk ratio: 1.8; 95% CI [1.2, 2.5]). Multimorbidity patterns involving CVD, especially for multimorbidity that includes CVD with comorbid anxiety and depression, should be considered in developing clinical trials to better inform medical decision-making and care for patients with CVD and comorbid conditions.Shu-Kay Ng, Sean A. Martin, Robert J. Adams, Peter O’Loughlin, and Gary A. Witter

The Association of Obstructive Sleep Apnea and Nocturnal Hypoxemia with Lipid Profiles in a Population-Based Study of Community-Dwelling Australian Men

Objective: To determine the association of obstructive sleep apnea and nocturnal hypoxemia with serum lipid profiles in unselected community-dwelling men. Methods: Cross-sectional data from participants of the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study (n=753) who underwent full in-home polysomnography (Embletta X100) was used. Triglycerides, high- (HDL), low-density lipoprotein (LDL), and total cholesterol were assessed on a fasting morning blood sample. Multivariable linear regression analyses assessed associations between lipids and continuous measures of nocturnal hypoxemia (oxygen desaturation index (3%) (ODI), apnea–hypopnea index (AHI), and rapid eye movement sleep apnea–hypopnea index (REM-AHI)), adjusted for chronic conditions, risk behavior and sociodemographic factors. Sensitivity analyses examined the effect of lipid lowering therapies on reported estimates. Effect modification was examined through stratification by waist circumference groups. Results: In 753 participants with mean (SD) age of 60.8 (10.9) years and waist circumference: 99.3 (11.6) cm, the prevalence of OSA (AHI≥10) was 52.6%. Overall, no significant associations between OSA metrics and lipid measures were found. Similarly, sensitivity analysis excluding lipid lowering therapies showed no significant associations. In analysis stratified by waist circumference (100cm), ODI (3%, unstandardized B: 0.027, 95% CI: 0.015–0.040), AHI (0.023, 0.012–0.033) and AHIREM (0.012, 0.001–0.022) were positively associated with serum triglycerides in participants with a normal waist circumference (<95cm). Conclusion: Obstructive sleep apnea metrics were positively associated with serum triglyceride levels in men with a normal waist circumference. Healthy weight individuals with OSA require clinical attention to improve cardiometabolic risk profiles.Layla B Guscoth, Sarah L Appleton, Sean A Martin, Robert J Adams, Yohannes A Melaku, Gary A Witter

Time-restricted feeding prevents ablation of diurnal rhythms in gastric vagal afferent mechanosensitivity observed in high-fat diet-induced obese mice

Mechanosensitive gastric vagal afferents (GVAs) are involved in the regulation of food intake. GVAs exhibit diurnal rhythmicity in their response to food related stimuli allowing time of day specific satiety signalling. This diurnal rhythmicity is ablated in high fat diet (HFD)-induced obesity. Time restricted feeding (TRF) has a strong influence on peripheral clocks. This study aimed to determine whether diurnal patterns in GVA mechanosensitivity are entrained by TRF.Eight-week old male C57BL/6 mice (N=256) were fed a standard laboratory diet (SLD) or HFD for 12wks. After 4wks diet acclimatisation the mice were fed either ad libitum or only during the light (zeitgeber (ZT)0-12) or dark phase (ZT12-24) for 8wks. A subgroup of mice from all conditions (N=8/condition) were placed in metabolic cages. After 12wks, ex vivo GVA recordings were taken at 3h intervals starting at ZT0.HFD mice gained more weight than SLD mice. TRF did not affect weight gain in the SLD mice but decreased weight gain in the HFD mice irrespective of the TRF period. In SLD mice diurnal rhythms in food intake were inversely associated with diurnal rhythmicity of GVA mechanosensitivity. These diurnal rhythms were entrained by the timing of food intake. In HFD mice diurnal rhythms in food intake and diurnal rhythmicity of GVA mechanosensitivity was dampened. Loss of diurnal rhythmicity in HFD-mice was abrogated by TRF.In conclusion, diurnal rhythmicity in GVA responses to food related stimuli can be entrained by food intake. TRF prevents the loss of diurnal rhythmicity that occurs in HFD-induced obesity.SIGNIFICANCE STATEMENTDiurnal control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong diurnal changes in food intake. Vagal afferents are involved in regulation of feeding behaviour, particularly meal size, and exhibit diurnal fluctuations in mechanosensitivity. These diurnal fluctuations in vagal afferent mechanosensitivity are lost in diet-induced obesity. This study provides evidence that time restricted feeding entrains diurnal rhythmicity in vagal afferent mechanosensitivity in lean and high fat diet-induced (HFD) obese mice and more importantly prevents the loss of rhythmicity in HFD-induced obesity. These data have important implications for the development of strategies to treat obesity.Stephen J. Kentish, George Hatzinikolas, Hui Li, Claudine L. Frisby, Gary A. Wittert and Amanda J. Pag

Effect of depression on health service utilisation in men: a prospective cohort study of Australian men aged 35 to 80 years

OBJECTIVES: To examine the relationship between depression burden, health service utilisation and depression diagnosis in community-based men. DESIGN: Prospective cohort study. SETTING: Community-based. PARTICIPANTS: Men aged 35-80 years at recruitment (2002-2005), randomly selected from the northern and western suburbs of Adelaide, Australia, without depression at baseline, who attended follow-up visits (2007-2010) (n=1464). PRIMARY AND SECONDARY OUTCOME MEASURES: Depression symptoms were categorised into high burden (total score of ≥13 for the Beck Depression Inventory (BDI) or ≥10 for the Centre for Epidemiologic Studies Depression Scale (CES-D) or low burden (<13 for the BDI or <10 for the CES-D). Diagnosed depression was determined by patient-reported physician diagnosis. Frequent general practitioner (GP) visits were those occurring 5+ times over the preceding year. Use of national medical and prescription services (Medicare Benefit Schedule and Pharmaceutical Benefit Scheme; MBS and PBS) was assessed through data linkage. RESULTS: Frequent attendance and depression diagnosis was more common in men with a high than low burden of depression symptoms (45.9% vs 29.3%-18.7% vs 1.9%, p<0.001). Depression diagnoses were also more common in frequent GP attenders compared with low-average attenders (5.1% vs 2.2%, p<0.001). Among men with high burden of symptoms, there was no age-adjusted or multi-adjusted difference for likelihood of depression diagnosis between non-regular and frequent GP attenders. Annualised MBS and PBS expenditure was highest for men with undiagnosed depression. CONCLUSIONS: Men with a high burden of depression symptoms have commensurate use of health services when compared with those with a low burden, but only half report a physician diagnosis of depression. Undiagnosed depression led to a higher usage of medical and prescription services.Sean Martin, Ian Zajac, Andrew Vincent, Robert J Adams, Sarah Appleton, Gary A Witter

Health behaviours of Australian men and the likelihood of attending a dedicated men's health service

Background: Redesigning primary health services may enhance timely and effective uptake by men. The primary aim of this study was to assess the likelihood of Australian men attending a dedicated men's health service (DMHS). The further aims were to better understand the reasons for their preferences and determine how health behaviours influence likelihood. Methods: A survey on health service use and preferences, health help-seeking behaviours, and the likelihood of attending a DMHS was administered by telephone to 1506 randomly selected men (median age 56 years, range 19-95). Likelihood of attending a DMHS was rated using a single item Likert scale where 0 was not at all likely and 10 highly likely. Respondents were classified by age ( = 65 years) and health status. Principal component analyses were used to define health behaviours, specifically help-seeking and delay/avoidance regarding visiting a doctor. Multivariable linear and logistic regression analyses were used to examine predictors of likelihood of attending a DMHS. Results: The mean likelihood of attending a DMHS was 5.8 (SD 3.3, median 6, moderate likelihood) and 21%, 26% and 23% of men rated likelihood as moderate, high and very high respectively. Being happy with their existing doctor was the most common reason (52%) for being less likely to attend a DMHS. In unadjusted analyses, younger men reported being more likely to attend a DMHS (p < 0.001) with older-sick men reporting being least likely (p < 0.001). Younger men were more likely than older men to score higher on delay/avoidance and were more likely to self-monitor. In the full model, men with current health concerns (p ≤ 0.01), who scored higher on delay/avoidance (p ≤ 0.0006), who were more likely to be information-seekers (p < 0.0001) and/or were motivated to change their health (p ≤ 0.0001) reported a higher likelihood of attending a DMHS irrespective of age and health status. Conclusions: Seventy percent of men reported a moderate or higher likelihood of attending a DMHS. As young healthy men are more likely than older men to display health behaviours that are associated with a higher likelihood of attending a DHMS, such as delay/avoidance, marketing a DMHS to such men may be of value.Andrew D. Vincent, Phoebe G. Drioli-Phillips, Jana Le, Lynette Cusack, Timothy J. Schultz, Margaret A. McGee, Deborah A. Turnbull, and Gary A. Witter

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.G. Ruel, S. A. Martin, J.-F. Lévesque, G. A. Wittert, R. J. Adams, S. L. Appleton, Z. Shi and A. W. Taylo

Deletion of Rptor in preosteoblasts reveals a role for the mammalian target of rapamycin complex 1 (mTORC1) complex in dietary-induced changes to bone mass and glucose homeostasis in female mice

The mammalian target of rapamycin complex 1 (mTORC1) complex is the major nutrient sensor in mammalian cells that responds to amino acids, energy levels, growth factors, and hormones, such as insulin, to control anabolic and catabolic processes. We have recently shown that suppression of the mTORC1 complex in bone-forming osteoblasts (OBs) improved glucose handling in male mice fed a normal or obesogenic diet. Mechanistically, this occurs, at least in part, by increasing OB insulin sensitivity leading to upregula- tion of glucose uptake and glycolysis. Given previously reported sex-dependent differences observed upon antagonism of mTORC1 signaling, we investigated the metabolic and skeletal effects of genetic inactivation of preosteoblastic-mTORC1 in female mice. Eight- week-old control diet (CD)-fed Rptor ob −/− mice had a low bone mass with a significant reduction in trabecular bone volume and trabecular number, reduced cortical bone thickness, and increased marrow adiposity. Despite no changes in body composition, CD-fed Rptor ob −/− mice exhibited significant lower fasting insulin and glucose levels and increased insulin sensitivity. Upon high-fat diet (HFD) feeding, Rptor ob −/− mice were resistant to a diet-induced increase in whole-body and total fat mass and protected from the development of diet-induced insulin resistance. Notably, although 12 weeks of HFD increased marrow adiposity, with minimal changes in both trabecular and cortical bone in the female control mice, marrow adiposity was significantly reduced in HFD-fed Rptor ob −/− compared to both HFD-fed control and CD-fed Rptor ob −/− mice. Collectively, our results demonstrate that mTORC1 func- tion in preosteoblasts is crucial for skeletal development and skeletal regulation of glucose homeostasis in both male and female mice. Importantly, loss of mTORC1 function in OBs results in metabolic and physiological adaptations that mirror a caloric restriction phenotype (under CD) and protects against HFD-induced obesity, associated insulin resistance, and marrow adiposity expansion. These results highlight the critical contribution of the skeleton in the regulation of whole-body energy homeostasisPawanrat Tangseefa, Sally K. Martin, Agnieszka Arthur, Vasilios Panagopoulos, Amanda J. Page, Gary A. Wittert ... et al

Associations of baseline obstructive sleep apnea and sleep macroarchitecture with cognitive function after 8 years in middle‐aged and older men from a community‐based cohort study

OnlinePublPrevious prospective studies examining associations of obstructive sleep apnea and sleep macroarchitecture with future cognitive function recruited older participants, many demonstrating baseline cognitive impairment. This study examined obstructive sleep apnea and sleep macroarchitecture predictors of visual attention, processing speed, and executive function after 8 years among younger community-dwelling men. Florey Adelaide Male Ageing Study participants (n = 477) underwent homebased polysomnography, with 157 completing Trail-Making Tests A and B and the Mini-Mental State Examination. Associations of obstructive sleep apnea (apnea– hypopnea index, oxygen desaturation index, and hypoxic burden index) and sleep macroarchitecture (sleep stage percentages and total sleep time) parameters with future cognitive function were examined using regression models adjusted for baseline demographic, biomedical, and behavioural factors, and cognitive task performance. The mean (standard deviation) age of the men at baseline was 58.9 (8.9) years, with severe obstructive sleep apnea (apnea–hypopnea index ≥30 events/h) in 9.6%. The median (interquartile range) follow-up was 8.3 (7.9–8.6) years. A minority of men (14.6%) were cognitively impaired at baseline (Mini-Mental State Examination score <28/30). A higher percentage of light sleep was associated with better TrailMaking Test A performance (B = 0.04, 95% confidence interval [CI] 0.06, 0.01; p = 0.003), whereas higher mean oxygen saturation was associated with worse performance (B = 0.11, 95% CI 0.02, 0.19; p = 0.012). While obstructive sleep apnea and sleep macroarchitecture might predict cognitive decline, future studies should consider arousal events and non-routine hypoxaemia measures, which may show associations with cognitive decline.Jesse L. Parker, Andrew Vakulin, Ganesh Naik, Yohannes Adama Melaku, David Stevens, Gary A. Wittert, Sean A. Martin, Peter G. Catcheside, Barbara Toson, Sarah L. Appleton, Robert J. Adam