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Hypertension disproportionately affects African Americans and is a risk factor for Alzheimer's disease (AD). We investigated the relationship of blood pressure (BP) with medial temporal lobe (MTL) dynamic network flexibility (a novel AD biomarker) and cognitive generalization in older African Americans. In a cross‐sectional study, 37 normotensive (systolic BP <130 mmHg, 82.5% F, 64.4 ± 4.9 years; 14.3 ± 2.1 years of education) versus 79 hypertensive (systolic BP ≥130 mmHg, 79.5% F, 66.8 ± 4.1 years; 14.0 ± 0.2 years of education) participants were enrolled. All participants completed a 10‐min resting‐state functional magnetic resonance imaging scan to assess MTL dynamic network flexibility and two generalization tasks to assess cognition. Anthropometrics and aerobic fitness (via 6‐min walk test) were also determined. There was no difference in BMI (29.7 ± 6.4 vs. 31.9 ± 6.3 kg/m2, p = 0.083) or aerobic fitness (15.5 ± 2.6 vs. 15.1 ± 2.6 mL/kg/min; p = 0.445) between normotensive and hypertensive groups. However, normotensive participants had higher MTL dynamic network flexibility compared to hypertensive participants (0.42 ± 0.23 vs. 0.32 ± 0.25 mL, p = 0.040), and this was associated with higher mean arterial blood pressure (r = −0.21, p = 0.036). Therefore, hypertensive older African Americans demonstrated lower MTL dynamic network flexibility compared to their normotensive counterparts independent of BMI and aerobic fitness. Further studies are required to determine how blood pressure mediates AD risk in African Americans. [ABSTRACT FROM AUTHOR]

To determine whether body fat and body mass index (BMI) affect the energy cost of walking (Cw; J/kg/m), ventilation, and gas exchange data from 205 adults (115 females; percent body fat range = 3.0%–52.8%; BMI range = 17.5–43.2 kg/m2) were obtained at rest and during treadmill walking at 1.34 m/s to calculate gross and net Cw. Linear regression was used to assess relationships between body composition indices, Cw, and standing metabolic rate (SMR). Unpaired t‐tests were used to assess differences between sex, and one‐way ANOVA was used to assess differences by BMI categories: normal weight, <25.0 kg/m2; overweight, 25.0–29.9 km/m2; and obese, ≥30 kg/m2. Net Cw was not related to body fat percent, fat mass, or BMI (all R2 ≤ 0.011). Furthermore, mean net Cw was similar by sex (male: 2.19 ± 0.30 J/kg/m; female: 2.24 ± 0.37 J/kg/m, p = 0.35) and across BMI categories (normal weight: 2.23 ± 0.36 J/kg/m; overweight: 2.18 ± 0.33 J/kg/m; obese: 2.26 ± 0.31, p = 0.54). Gross Cw and SMR were inversely associated with percent body fat, fat mass, and BMI (all R2 between 0.033 and 0.270; all p ≤ 0.008). In conclusion, Net Cw is not influenced by body fat percentage, total body fat, and BMI and does not differ by sex. [ABSTRACT FROM AUTHOR]

Obesity over‐activates the classical arm of the renin‐angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin‐converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high‐fat (HF) diet for 16 weeks. At the eighth week, the HF‐fed animals were divided into four subgroups—sedentary (HF), treated with enalapril (HF‐E), exercise training protocol (HF‐T), and combined interventions (HF‐ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF‐T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity‐induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training. [ABSTRACT FROM AUTHOR]

Obesity is a global health problem characterized by excessive fat accumulation, driven by adipogenesis and lipid accumulation. Long non‐coding RNAs (lncRNAs) have recently been implicated in regulating adipogenesis and adipose tissue function. Mouse lncRNA U90926 was previously identified as a repressor of in vitro adipogenesis in 3T3‐L1 preadipocytes. Consequently, we hypothesized that, in vivo, U90926 may repress adipogenesis, and hence its deletion would increase weight gain and adiposity. We tested the hypothesis by applying U90926‐deficient (U9‐KO) mice to a high‐throughput phenotyping pipeline. Compared with WT, U9‐KO mice showed no major differences across a wide range of behavioral, neurological, and other physiological parameters. In mice fed a standard diet, we have found no differences in obesity‐related phenotypes, including weight gain, fat mass, and plasma concentrations of glucose, insulin, triglycerides, and free fatty acids, in U9‐KO mice compared to WT. U90926 deficiency lacked a major effect on white adipose tissue morphology and gene expression profile. Furthermore, in mice fed a high‐fat diet, we found increased expression of U90926 in adipose tissue stromal vascular cell fraction, yet observed no effect of U90926 deficiency on weight gain, fat mass, adipogenesis marker expression, and immune cell infiltration into the adipose tissue. These data suggest that the U90926 lacks an essential role in obesity‐related phenotypes and adipose tissue biology in vivo. [ABSTRACT FROM AUTHOR]

Leptin an adipokine with potent effects on energy balance and body weight plays an important role in defining bone architecture in growing mammals. However, major changes in body weight can also influence morphology of trabecular and cortical bone. Therefore, we examined the impact of leptin deficiency on tibia and vertebral body 3D bone architecture independent of changes in body weight. Furthermore, advances in computational 3D image analysis suggest that average morphological values may mask regional specific differences in trabecular bone thickness. The study utilized leptin‐deficient Ob/Ob mice (n = 8) weight‐paired to C57BL/6 (C57) control mice (n = 8) which were split into either lean or obese groups for 24 ± 2 weeks. Whole tibias and L3 vertebrae were fixed before high resolution microcomputed tomography (μCT) scanning was performed. Leptin deficiency independent of body weight reduced tibia cortical bone volume, trabecular bone volume/tissue volume, number, and mineral density. Mean tibia trabecular thickness showed no significant differences between all groups; however, significant changes in trabecular thickness were found when analyzed by region. This study demonstrates that leptin deficiency significantly impacts tibia and vertebral body trabecular and cortical bone 3D architecture independent of changes in body weight. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) and obesity are common illnesses characterized by glucose metabolism issues and excessive weight gain. Breastfeeding is the best way to feed a newborn up to 6 months old and it has been shown to reduce the risk of diabetes and obesity later in life due to its nutritional properties. The purpose of this study was to investigate the effects of breastfeeding, formula feeding, and formula‐plus breastfeeding (mix‐feeding) on the anthropometric indices, metabolic variables, and the expression level of obesity and diabetes‐predisposing genes of healthy infants. A total of 150 healthy infants were enrolled in this cross‐sectional study. All infants (aged 24 months) were divided into three groups based on the type of feeding, breastfeeding, formula feeding, and mix‐feeding. The anthropometric indices, glycemic indexes, lipid profile, and the expression levels of acetyl‐coenzyme A carboxylase beta (ACACB), brain‐derived neurotrophic factor (BDNF), liver X receptor α (LXR‐α), peroxisome proliferator‐activated receptor γ (PPAR‐γ), and phosphatase and tensin homolog (PTEN) genes were measured in all infants using reverse transcription‐polymerase chain reaction (RT‐PCR) method. The anthropometric indices including weight, height, head circumference, insulin, total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C), and high‐density lipoprotein cholesterol (HDL‐C) were lower in the breastfeeding infants in comparison to other groups. As well, the expression level of the ACACB gene was significantly downregulated in breastfeeding infants, while the PPAR‐γ gene was significantly upregulated, but the expression levels of LXR‐ α, PTEN and BDNF did not change significantly across groups. Breastfeeding compared to formula feeding had positive effects on anthropometric indices, metabolic variables, and diabetes‐predisposing genes. [ABSTRACT FROM AUTHOR]

Repeated activation of the beta 3 adrenergic receptor (β3AR) with the agonist CL 316,243 (CL) results in remodeling of white adipose tissue (WAT) characterized by increased mitochondrial enzymes and expression of uncoupling protein 1 (UCP1). β3AR activation also has profound acute metabolic effects including rapidly decreasing blood glucose, secondary to fatty acid‐induced increases in insulin, and increasing energy expenditure. The acute (single dose) effects of β3AR activation have largely been examined in treatment naive animals and under room temperature housing conditions. The current study examined if repeated CL treatment would lead to an attenuation of acute metabolic effects of CL treatment under thermoneutral housing conditions and if this could be rescued with cilostamide, a phosphodiesterase inhibitor. We provide evidence demonstrating that the acute effects of CL to increase serum fatty acids and insulin and reduce blood glucose, but not increases in energy expenditure, are attenuated in mice following repeated treatment with CL. This occurs in parallel with reductions in indices of protein kinase A signaling in WAT including the phosphorylation of hormone sensitive lipase. The findings of attenuated serum fatty acid, insulin, and blood glucose responses were confirmed in both high‐fat fed and UCP1−/− mice repeatedly treated with CL. Desensitization to CL in mice was rescued by cilostamide. Herein, we provide evidence that the glucose lowering, but not thermogenesis inducing, effects of CL are attenuated with repeated treatment and can be rescued by cilostamide. The findings of this study point toward novel adjunct treatment approaches that could be used to maximize therapeutic, glucose lowering effects of β3AR agonists. [ABSTRACT FROM AUTHOR]

The metabolic syndrome is a cluster of conditions that increase an individual's risk of developing diseases. Being physically active throughout life is known to reduce the prevalence and onset of some aspects of the metabolic syndrome. Furthermore, previous studies have demonstrated that an individual's gut microbiome composition has a large influence on several aspects of the metabolic syndrome. However, the mechanism(s) by which physical activity may improve metabolic health are not well understood. We sought to determine if endurance exercise is sufficient to prevent or ameliorate the development of the metabolic syndrome and its associated diseases. We also analyzed the impact of physical activity under metabolic syndrome progression upon the gut microbiome composition. Utilizing whole‐body low‐density lipoprotein receptor (LDLR) knockout mice on a "Western Diet," we show that long‐term exercise acts favorably upon glucose tolerance, adiposity, and liver lipids. Exercise increased mitochondrial abundance in skeletal muscle but did not reduce liver fibrosis, aortic lesion area, or plasma lipids. Lastly, we observed several changes in gut bacteria and their novel associations with metabolic parameters of clinical importance. Altogether, our results indicate that exercise can ameliorate some aspects of the metabolic syndrome progression and alter the gut microbiome composition. [ABSTRACT FROM AUTHOR]

Excessive adiposity is associated with altered oxygen tension and comorbidities in humans. In contrast, marine mammals have high adiposity with no apparent detrimental effects. However, partial pressure of oxygen (Po2) in their subcutaneous adipose tissue (blubber) and its relationship with fatness have not been reported. We measured Po2 and temperature at different blubber depths in 12 healthy juvenile grey seals. Fatness was estimated from blubber thickness and morphometric parameters. Simultaneously, we monitored breathing pattern; heart rate and arterial blood saturation with a pulse oximeter; and relative changes in total hemoglobin, deoxyhemoglobin, and oxyhemoglobin in blubber capillaries using near‐infrared spectroscopy (NIRS) as proxies for local oxygenation changes. Blubber Po2 ranged from 14.5 to 71.4 mmHg (39.2 ± 14.1 mmHg), which is similar to values reported in other species. Blubber Po2 was strongly and negatively associated with fatness (LME: p < 0.0001, R2marginal = 0.53, R2conditional = 0.64, n = 10), but not with blubber depth. No other parameters explained variability in Po2, suggesting arterial blood and local oxygen delivery did not vary within and between measurements. The fall in blubber Po2 with increased fatness in seals is consistent with other animal models of rapid fat deposition. However, the Po2 levels at which blubber becomes hypoxic and consequences of low blubber Po2 for its health and function, particularly in very fat individuals, remain unknown. How seals avoid detrimental effects of low oxygen tension in adipose tissue, despite their high and fluctuating adiposity, is a fruitful avenue to explore. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether time‐restricted eating (TRE), also known as time‐restricted feeding, was an effective dietary strategy for reducing fat mass and preserving fat‐free mass while evaluating changes in cardiometabolic biomarkers, hormones, muscle performance, energy intake, and macronutrient intake after aerobic and resistance exercise training in physically inactive and overweight or obese adults. This study was a randomized, controlled trial. Overweight and obese adults (mean ± SD; age: 44 ± 7 years; body mass index [BMI]: 29.6 ± 2.6 kg/m2; female: 85.7%) were randomly assigned to a TRE or normal eating (NE) dietary strategy group. The TRE participants consumed all calories between 12:00 p.m. and 8:00 p.m., whereas NE participants maintained their dietary habits. Both groups completed 8 weeks of aerobic exercise and supervised resistance training. Body composition, muscle performance, energy intake, macronutrient intake, physical activity, and physiological variables were assessed. A total of 21 participants completed the study (NE: n = 10; TRE: n = 11). A mild energy restriction was observed for TRE (~300 kcal/day, 14.5%) and NE (~250 kcal/day, 11.4%). Losses of total body mass were significantly greater for TRE (3.3%) relative to NE (0.2%) pre‐ to post‐intervention, of which TRE had significantly greater losses of fat mass (9.0%) compared to NE (3.3%). Lean mass increased during the intervention for both TRE (0.6%) and NE (1.9%), with no group differences. These data support the use of TRE and concurrent exercise training as a short‐term dietary strategy for reducing fat mass and increasing lean mass in overweight and obese adults. [ABSTRACT FROM AUTHOR]

Very little is known about how metabolic health status, insulin resistance or metabolic challenges modulate the endocannabinoid (eCB) or polyunsaturated fatty acid (PUFA)‐derived oxylipin (OxL) lipid classes. To address these questions, plasma eCB and OxL concentrations were determined at rest, 10 and 20 min during an acute exercise bout (30 min total, ~45% of preintervention V̇O2peak, ~63 W), and following 20 min recovery in overnight‐fasted sedentary, obese, insulin‐resistant women under controlled diet conditions. We hypothesized that increased fitness and insulin sensitivity following a ~14‐week training and weight loss intervention would lead to significant changes in lipid signatures using an identical acute exercise protocol to preintervention. In the first 10 min of exercise, concentrations of a suite of OxL diols and hydroxyeicosatetraenoic acid (HETE) metabolites dropped significantly. There was no increase in 12,13‐DiHOME, previously reported to increase with exercise and proposed to activate muscle fatty acid uptake and tissue metabolism. Following weight loss intervention, exercise‐associated reductions were more pronounced for several linoleate and alpha‐linolenate metabolites including DiHOMEs, DiHODEs, KODEs, and EpODEs, and fasting concentrations of 9,10‐DiHODE, 12,13‐DiHODE, and 9,10‐DiHOME were reduced. These findings suggest that improved metabolic health modifies soluble epoxide hydrolase, cytochrome P450 epoxygenase (CYP), and lipoxygenase (LOX) systems. Acute exercise led to reductions for most eCB metabolites, with no evidence for concentration increases even at recovery. It is proposed that during submaximal aerobic exercise, nonoxidative fates of long‐chain saturated, monounsaturated, and PUFAs are attenuated in tissues that are important contributors to the blood OxL and eCB pools. [ABSTRACT FROM AUTHOR]

Obesity is a complex metabolic disorder that often leads to a decrease in insulin sensitivity, chronic inflammation, and overall decline in human health and well‐being. In mouse skeletal muscle, obesity has been shown to impair muscle regeneration after injury; however, the mechanism underlying these changes has yet to be determined. To test whether there is a negative impact of obesity on satellite cell (SC) decisions and behaviors, we fed C57BL/6 mice normal chow (NC, control) or a high‐fat diet (HFD) for 10 weeks and performed SC proliferation and differentiation assays in vitro. SCs from HFD mice formed colonies with smaller size (p <.001) compared to those from NC mice, and this decreased proliferation was confirmed (p <.05) by BrdU incorporation. Moreover, in vitro assays showed that HFD SCs exhibited diminished (p <.001) fusion capacity compared to NC SCs. In single fiber explants, a higher ratio of SCs experienced apoptotic events (p <.001) in HFD mice compared to that of NC‐fed mice. In vivo lineage tracing using H2B‐GFP mice showed that SCs from HFD treatment also cycled faster (p <.001) than their NC counterparts. In spite of all these autonomous cellular effects, obesity as triggered by high‐fat feeding did not significantly impair muscle regeneration in vivo, as reflected by the comparable cross‐sectional area (p >.05) of the regenerating fibers in HFD and NC muscles, suggesting that other factors may mitigate the negative impact of obesity on SCs properties. [ABSTRACT FROM AUTHOR]

Obese individuals exhibit a diminished muscle protein synthesis response to nutrient stimulation when compared with their lean counterparts. However, the effect of obesity on exercise-stimulated muscle protein synthesis remains unknown. Nine lean (23.5 ± 0.6 kg/m2) and 8 obese (33.6 ± 1.2 kg/m2) physically active young adults participated in a study that determined muscle protein synthesis and intracellular signaling at rest and following an acute bout of resistance exercise. Mixed muscle protein synthesis was determined by combining stable isotope tracer ([13C6]phenylalanine) infusion with serial biopsies of the vastus lateralis. A unilateral leg resistance exercise model was adopted so that resting and postexercise measurements of muscle protein synthesis could be obtained simultaneously. Obesity was associated with higher basal levels of serum insulin (P < 0.05), plasma triacylglycerol (P < 0.01), plasma cholesterol (P < 0.01), and plasma CRP (P < 0.01), as well as increased insulin resistance determined by HOMA-IR (P < 0.05). However, resting and postexercise rates of muscle protein synthesis were not significantly different between lean and obese participants (P = 0.644). Furthermore, resistance exercise stimulated muscle protein synthesis (~50% increase) in both groups (P < 0.001), with no difference between lean and obese (P = 0.809). Temporal increases in the phosphorylation of intracellular signaling proteins (AKT/4EBP1/p70S6K) were observed within the exercised leg (P < 0.05), with no differences between lean and obese. These findings suggest a normal anabolic response to muscle loading in obese young adults. [ABSTRACT FROM AUTHOR]

The intestinal epithelium is continuously regenerated by cell renewal of intestinal epithelial stem cells (IESCs) located in the intestinal crypts. Obesity affects this process and results in changes in the size and cellular make-up of the tissue, but it remains unknown if there are sex differences in obesity-induced alterations in IESC proliferation and differentiation. We fed male and female mice a 60% high-fat diet (HFD) or a 10% low-fat diet (LFD) for 3 months and investigated the differences in (1) the expression of markers of different intestinal epithelial cell types in vivo, and (2) lasting effects on IESC growth in vitro. We found that the growth of IESCs in vitro were enhanced in females compared with males. HFD induced similar in vivo changes and in vitro early growth of IESCs in males and females. The IESCs isolated and grown in vitro from females, though, showed an enhanced growth that was independent of obesity. To determine whether this effect was driven by sex steroid hormones, we used primary intestinal crypts isolated from male and female mice and investigated the differences in (1) the expression of steroid hormone receptors, and (2) cell proliferation in response to steroid hormones. We found that estrogen receptor α was expressed in crypts from both sexes, but estrogen had no effect on proliferation in either sex. These results suggest that obesity similarly effects IESCs in males and females, but IESCs in females have greater proliferation ability than males, but this is not driven by a direct effect of sex steroid hormones on IESCs or other crypt cells that provide essential niche support for IESCs. [ABSTRACT FROM AUTHOR]

Adipokines and other biomarkers were previously identified with roles in energy expenditure, appetite, satiety, and adiposity. Therefore, we investigated whether dietary weight loss-induced changes in adipokines and other biomarkers known to play a role in weight regulation or energy expenditure could predict weight regain in people with overweight and obesity. In this randomized controlled trial 26 males and 30 females (BMI: 28-35 kg/m²) followed either a low-calorie diet (LCD; 1250 kcal/day) for 12 weeks or a very-low-calorie diet (VLCD; 500 kcal/day) for 5 weeks followed by a weight stable period of 4 weeks (dietary intervention (DI) period) and a 9-month follow-up period. Blood samples were taken before and after each period to measure FFA, TAG, total cholesterol, insulin, glucose, angiotensin-converting enzyme (ACE) activity, IL-6, RBP4, apelin, leptin, adiponectin, vaspin, and nesfatin-1 concentrations. Weight loss was similar between groups (LCD: -8.2 ± 0.5 kg; VLCD: -8.9 ± 0.4 kg, P = 0.30). Only changes in ACE activity, FFA and RBP4 concentrations during DI were correlated with weight regain in the whole group (r = -0.299, P = 0.030, r = -0.274, P = 0.047, and r = 0.357, P = 0.008, respectively). Together they explained 28% (r = 0.532) of weight regain variation. Dietary weight loss-induced changes in ACE activity, FFA and RBP4 independently contribute to weight regain prediction. [ABSTRACT FROM AUTHOR]

Noncoding RNAs are emerging as regulators of inflammatory and metabolic processes. There is evidence to suggest that miRNA155 (miR155) may be linked to inflammation and processes associated with adipogenesis. We examined the impact of global miRNA-155 deletion (miR155-/- ) on the development of high-fat diet (HFD)-induced obesity. We hypothesized that loss of miR155 would decrease adipose tissue inflammation and improve the metabolic profile following HFD feedings. Beginning at 4-5 weeks of age, male miR155-/- and wild-type (WT) mice (n = 13-14) on a C57BL/6 background were fed either a HFD or low-fat diet for 20 weeks. Body weight was monitored throughout the study. Baseline and terminal body composition was assessed by DEXA analysis. Adipose tissue mRNA expression (RTqPCR) of macrophage markers (F4/80, CD11c, and CD206) and inflammatory mediators (MCP-1 and TNF-α) as well as adiponectin were measured along with activation of NFκB-p65 and JNK and PPAR-γ. Adipose tissue fibrosis was assessed by picrosirius red staining and western blot analysis of Collagen I, III, and VI. Glucose metabolism and insulin resistance were assessed by Homeostatic Model Assessment - Insulin Resistance (HOMAIR), and a glucose tolerance test. Compared to WT HFD mice, miR155-/- HFD mice displayed similar body weights, yet reduced visceral adipose tissue accumulation. However, miR155-/- HFD displayed exacerbated adipose tissue fibrosis and decreased PPAR-γ protein content. The loss of miR155 did not affect adipose tissue inflammation or glucose metabolism. In conclusion, miR155 deletion did not attenuate the development of the obese phenotype, but adipose tissue fibrosis was exacerbated, possibly through changes to adipogenic processes. [ABSTRACT FROM AUTHOR]

Both the history of obesity and weight loss may change how menopause affects metabolic health. The purpose was to determine whether obesity and/or weight loss status alters energy balance ( EB) and subsequent weight gain after the loss of ovarian function. Female lean and obese Wistar rats were randomized to 15% weight loss ( WL) or ad libitum fed controls ( CON). After the weight loss period, WL rats were kept in EB at the reduced weight for 8 weeks prior to ovariectomy ( OVX). After OVX, all rats were allowed to eat ad libitum until weight plateaued. Energy intake ( EI), spontaneous physical activity, and total energy expenditure ( TEE) were measured with indirect calorimetry before OVX, immediately after OVX, and after weight plateau. Changes in energy intake ( EI), TEE, and weight gain immediately after OVX were similar between lean and obese rats. However, obese rats gained more total weight and fat mass than lean rats over the full regain period. Post- OVX, EI increased more ( P ≤ 0.03) in WL rats (58.9 ± 3.5 kcal/d) than CON rats (8.5 ± 5.2 kcal/d), and EI partially normalized (change from pre OVX: 20.5 ± 4.2 vs. 1.5 ± 4.9 kcal/day) by the end of the study. As a result, WL rats gained weight (week 1:44 ± 20 vs. 7 ± 25 g) more rapidly (mean = 44 ± 20 vs. 7 ± 25 g/week; P < 0.001) than CON. Prior obesity did not affect changes in EB or weight regain following OVX, whereas a history of weight loss prior to OVX augmented disruptions in EB after OVX, resulting in more rapid weight regain. [ABSTRACT FROM AUTHOR]

Suppressed parasympathetic function is commonly present in cardiovascular diseases, aging, obesity, and various other health conditions. Impaired parasympathetic action is known as a detrimental factor and contributes to the adverse outcomes in these conditions. However, the underlying mechanisms remain to be fully addressed. In this study, using high-fat diet (HFD)-induced obese mice as a model, the potential peripheral mechanisms underlying the impaired parasympathetic vagal control of the heart was examined. The HFD induced obesity and metabolic disorder in mice. These obese mice exhibited an attenuated response in heart rate to vagal stimulation, indicating impairment of peripheral parasympathetic activity in the heart. In cholinergic function-related proteins in the atria, protein levels of choline transporter and vesicular acetylcholine transporter were not decreased but increased, and type 2 muscarinic receptors showed a trend toward a reduction in HFD mice atria as compared with regular diet (RD) mice controls. While the protein level of acetylcholinesterase was not different, butyrylcholinesterase (BChE) protein level showed a twofold increase in HFD mice atria as compared with RD mice. Functionally, inhibition of BChE activity partially and significantly improved the attenuated response in heart rate to vagal stimulation in HFD mice. Collectively, these data suggest that increased BChE activity in the atria may contribute to the decreased parasympathetic function in HFD-induced obese mice. [ABSTRACT FROM AUTHOR]

Mice are commonly used as animal models to study human metabolic diseases, but experiments are typically performed at room temperature, which is far below their thermoneutral zone and is associated with elevated heart rate, food intake, and energy expenditure. We set out to study how ambient temperature affects glucose tolerance and insulin sensitivity in control and obese male mice. Adult male C57BL/6J mice were housed at room temperature (23°C) for 6 weeks and fed either control or high fat diet. They were then fasted for 6 h before glucose or insulin tolerance tests were performed at 15, 20, 25, or 30°C. To ensure that behavioral thermoregulation did not counterbalance the afflicted ambient temperatures, oxygen consumption was determined on mice with the same thermoregulatory opportunities as during the tests. Decreasing ambient temperatures increased oxygen consumption and body mass loss during fasting in both groups. Mice fed high fat diet had improved glucose tolerance at 30°C and increased levels of fasting insulin followed by successive decrease of fasting glucose. However, differences between control and high-fat diet mice were present at all temperatures. Ambient temperature did not affect glucose tolerance in control group and insulin tolerance in either of the groups. Ambient temperature affects glucose metabolism in mice and this effect is phenotype specific. [ABSTRACT FROM AUTHOR]

Stress hyperglycemia following trauma has been shown to potentiate morbidity and mortality. Glucose control in obese patients can be challenging due to insulin resistance. Thus, understanding the mechanisms for glucose generation following hemorrhage may provide important insights into alternative options for glycemic control in obesity. Obesity is characterized by elevated glycogen and increased hepatic β2-adrenergic activity, which play major roles in glucose production after hemorrhage. We hypothesized that, in obesity, hepatic glycogenolysis is enhanced during stress hyperglycemia due to increased hepatic β2-adrenoceptor activation. Hemorrhage was performed in conscious lean Zucker (LZ) and obese Zucker rats (OZ) by withdrawing 35% total blood volume over 10 min. Liver glycogen content and plasma levels of glucose, insulin, and glucagon were measured before and 1 h after hemorrhage. The hyperglycemic response was greater in OZ as compared to LZ, but glycogen content was similarly reduced in both groups. Subsequently, OZ had a greater fall in insulin compared to LZ. Glucagon levels were significantly increased 1 h after hemorrhage in LZ but not in OZ. To test the direct adrenergic effects on the liver after hemorrhage, we treated animals before hemorrhage with a selective β2-adrenoceptor antagonist, ICI-118,551 (ICI; 2 mg/kg/h, i.v.). After hemorrhage, ICI significantly reduced hyperglycemia in both LZ and OZ, independent of hormonal changes, but there was a significantly decreased hepatic glycogenolysis in OZ. These results suggest that the hemorrhage-induced hepatic glycogenolysis is likely glucagon-dependent in LZ, whereas the β2-adrenoceptor plays a greater role in OZ. [ABSTRACT FROM AUTHOR]

Disruption of KSR2 in humans and mice decreases metabolic rate and induces obesity, coincident with dysregulation of glucose homeostasis. Relative to wild-type mice, ksr2 −/− mice are small prior to weaning with normal glucose tolerance at 6 weeks of age, but demonstrate excess adiposity by 9 weeks and glucose intolerance by 12-14 weeks. Defects in AICAR tolerance, a measure of whole-body AMPK activation, are detectable only when ksr2 −/− mice are obese. Food restriction prevents the obesity of adult ksr2 −/− mice and normalizes glucose and AICAR sensitivity. Obesity and glucose intolerance return when ad lib feeding is restored to the diet-restricted mice, indicating that glucose dysregulation is secondary to obesity in ksr2 −/− mice. The phenotype of C57 BL/6 ksr2 −/− mice, including obesity and obesity-related dysregulation of glucose homeostasis, recapitulates that of humans with KSR2 mutations, demonstrating the applicability of the C57 BL/6 ksr2 −/− mouse model to the study of the pathogenesis of human disease. These data implicate KSR2 as a physiological regulator of glucose metabolism during development affecting energy sensing, insulin signaling, and lipid storage, and demonstrate the value of the C57 BL/6 ksr2 −/− mouse model as a unique and relevant model system in which to develop and test therapeutic targets for the prevention and treatment of obesity, type 2 diabetes, and obesity-related metabolic disorders. [ABSTRACT FROM AUTHOR]

Maternal obesity during pregnancy has a detrimental impact on offspring renal development and function. This is pertinent to Indigenous Australians as they are twice as likely as non‐Indigenous Australians to develop chronic kidney disease (CKD). The aim of this study was to examine whether there was an association between maternal adiposity and fetal kidney growth in late gestation (>28 weeks) and kidney function in infants, <2.5 years of age, from the Gomeroi gaaynggal cohort. Pre‐pregnancy body mass index (BMI) was recorded at the first prenatal visit and maternal adiposity indicators (percent body fat and visceral fat area) measured at >28 weeks gestation by bioelectrical impedance analysis. Fetal kidney structure was assessed by ultrasound. Renal function indicators (urinary albumin:creatinine and protein:creatinine) were measured in infants from a spot urine collection from nappies. Multiple linear regression and multi‐level mixed effects linear regression models with clustering were used to account for repeated measures of urine. 147 mother–child pairs were examined. Estimated fetal weight (EFW), but not fetal kidney size, was positively associated with maternal adiposity and pre‐pregnancy BMI. When adjusted for smoking, combined kidney volume relative to EFW was negatively associated with maternal percentage body fat. Infant kidney function was not influenced by maternal adiposity and pre‐pregnancy BMI (n = 84 observations). Current findings show that Indigenous babies born to obese mothers have reduced kidney size relative to EFW. We suggest that these babies are experiencing a degree of glomerular hyperfiltration in utero, and therefore are at risk of developing CKD in later life, especially if their propensity for obesity is maintained. Although no impact on renal function was observed at <2.5 years of age, long‐term follow‐up of offspring is required to evaluate potential later life impacts. [ABSTRACT FROM AUTHOR]

Palatable hypercaloric feeding has been associated with angiotensin‐II type 1 receptor (AT1R) stimulation and cardiac remodeling. This study analyzed whether AT1R antagonism attenuates cardiac remodeling in rats subjected to a palatable hypercaloric diet. Male Wistar‐Kyoto rats were subjected to a commercial standard rat chow (CD) or a palatable hypercaloric diet (HD) for 35 weeks and then allocated into four groups: CD, CL, HD, and HL; L groups received losartan in drinking water (30 mg/kg/day) for 5 weeks. Body weight, adiposity, and glycemia were evaluated. The cardiovascular study included echocardiography, and myocardial morphometric and ultrastructural evaluation. Myocardial collagen isoforms Type I and III were analyzed by Western blot. Both HD and HL had higher adiposity than their respective controls. Cardiomyocyte cross‐sectional‐area (CD 285 ± 49; HD 344 ± 91; CL 327 ± 49; HL 303 ± 49 μm2) and interstitial collagen fractional area were significantly higher in HD than CD and unchanged by losartan. HD showed marked ultrastructural alterations such as myofilament loss, and severe mitochondrial swelling. CL presented higher Type I collagen expression when compared to CD and HL groups. The ultrastructural changes and type I collagen expression were attenuated by losartan in HL. Losartan attenuates systolic dysfunction and ultrastructural abnormalities without changing myocardial interstitial remodeling in rats subjected to a palatable hypercaloric diet. Diet reduced type I collagen expression in the heart. The ultrastructural changes and type I collagen expression promoted by high‐fat and hypercaloric diet were attenuated by AT1 antagonism. [ABSTRACT FROM AUTHOR]