Insulin-mediated increases in arterial baroreflex control of muscle sympathetic nerve activity following meal intake in humans [abstract]

Animal studies indicate that insulin enhances arterial baroreflex (ABR) control of sympathetic nerve activity (SNA); however, the extent to which these findings can be extrapolated to humans is unknown. To begin to address this, we utilized a mixed meal as a physiological method to evoke sustained increases in plasma insulin

Endurance or sprint interval exercise, & metformin treatment differently modify insulin-induced vasodilation in skeletal muscle arterioles of obese insulin resistant rats

A key contributor to insulin-mediated glucose uptake is insulin-induced vasodilation of skeletal muscle arterioles, which is impared with obesity and Type 2 diabetes (T2D). Abnormalities in the vascular reactivity to insulin can limit perfusion, and delivery of glucose and insulin to muscle tissue. In human patients with T2D, exercise improves insulin sensitivity and glucose uptake T2D. Furthermore, we have previously shown that daily exercise prevents impairments in insulin-induced vasodilation in OLETF rats. However, the efficacy of exercise interventions which utilize different muscle recruitment patterns (i.e. aerobic vs. sprint training) to ameliorate or reverse impairments in microvascular insulin reactivity has not been elucidated. The current ADA standard of care for T2D is treatment with metformin in combination with a diet and exercise program. Therefore, we studied the effects of endurance exercise and interval sprint training with and without metformin on the vasoreactivity to insulin in skeletal muscle arterioles from red and white muscles

Increased aerobic capacity reduces susceptibility to acute high‐fat diet‐induced weight gain

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134165/1/oby21564.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134165/2/oby21564_am.pd

Divergent role of nitric oxide in insulin‐stimulated aortic vasorelaxation between low‐ and high‐intrinsic aerobic capacity rats

Low‐intrinsic aerobic capacity is associated with increased risk for cardiovascular and metabolic diseases and is a strong predictor of early mortality. The effects of intrinsic aerobic capacity on the vascular response to insulin are largely unknown. We tested the hypothesis that rats selectively bred for a low capacity to run (LCR) exhibit vascular dysfunction and impaired vascular reactivity to insulin compared to high capacity running (HCR) rats. Mature female LCR (n = 21) and HCR (n = 17) rats were maintained under sedentary conditions, and in vitro thoracic aortic vascular function was assessed. LCR exhibited greater body mass (13%), body fat (35%), and subcutaneous, perigonadal, and retroperitoneal adipose tissue mass, than HCR. During an intraperitoneal glucose tolerance test, glucose area under the curve (AUC) was not different but insulin AUC was 2‐fold greater in LCR than HCR. Acetylcholine and insulin‐stimulated aortic vasorelaxation was significantly greater in LCR (65.2 ± 3.8%, and 32.7 ± 4.1%) than HCR (55.0 ± 3.3%, and 16.7 ± 2.8%). Inhibition of nitric oxide synthase (NOS) with L‐NAME entirely abolished insulin‐mediated vasorelaxation in the aorta of LCR, with no effect in HCR. LCR rats exhibited greater expression of Insulin Receptor protein, lower Endothelin Receptor‐A protein, a down‐regulation of transcripts for markers of immune cell infiltration (CD11C, CD4, and F4/80) and up‐regulation of pro‐atherogenic inflammatory genes (VCAM‐1 and MCP‐1) in the aorta wall. Contrary to our hypothesis, low‐aerobic capacity was associated with enhanced aortic endothelial function and NO‐mediated reactivity to insulin, despite increased adiposity and evidence of whole body insulin resistance.Rats selectively bred for low‐aerobic capacity displayed enhanced aortic endothelial function and nitric oxide‐mediated insulin‐stimulated vasorelaxation, despite increased adiposity and evidence of whole body insulin resistance. The vascular reactivity to insulin in high‐intrinsic aerobic capacity rats was independent of nitric oxide. Our findings demonstrate that endothelial and nitric oxide insulin‐mediated vasomotor function in the rat aorta is not always associated with aerobic capacity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112223/1/phy212459.pd

Preconceptional, Gestational, and Lactational Exposure to an Unconventional Oil and Gas Chemical Mixture Alters Energy Expenditure in Adult Female Mice

Previous studies conducted in our laboratory have found altered adult health outcomes in animals with prenatal exposure to environmentally relevant levels of unconventional oil and gas (UOG) chemicals with endocrine-disrupting activity. This study aimed to examine potential metabolic health outcomes following a preconception, prenatal and postnatal exposure to a mixture of 23 UOG chemicals. Prior to mating and from gestation day 1 to postnatal day 21, C57BL/6J mice were developmentally exposed to a laboratory-created mixture of 23 UOG chemicals in maternal drinking water. Body composition, spontaneous activity, energy expenditure, and glucose tolerance were evaluated in 7-month-old female offspring. Neither body weight nor body composition differed in 7-month female mice. However, females exposed to 1.5 and 150 μg/kg/day UOG mix had lower total and resting energy expenditure within the dark cycle. In the light cycle, the 1,500 μg//kg/day group had lower total energy expenditure and the 1.5 μg/kg/day group had lower resting energy expenditure. Females exposed to the 150 μg/kg/day group had lower spontaneous activity in the dark cycle, and females exposed to the 1,500 μg/kg/day group had lower activity in the light cycle. This study reports for the first time that developmental exposure to a mixture of 23 UOG chemicals alters energy expenditure and spontaneous activity in adult female mice

Exercise and Omega-3 Polyunsaturated Fatty Acid Supplementation for the Treatment of Hepatic Steatosis in Hyperphagic OLETF Rats

Background and Aims. This study examined if exercise and omega-3 fatty acid (n3PUFA) supplementation is an effective treatment for hepatic steatosis in obese, hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Methods. Male OLETF rats were divided into 4 groups (n=8/group): (1) remained sedentary (SED), (2) access to running wheels; (EX) (3) a diet supplemented with 3% of energy from fish oil (n3PUFA-SED); and (4) n3PUFA supplementation plus EX (n3PUFA+EX). The 8 week treatments began at 13 weeks, when hepatic steatosis is present in OLETF-SED rats. Results. EX alone lowered hepatic triglyceride (TAG) while, in contrast, n3PUFAs failed to lower hepatic TAG and blunted the ability of EX to decrease hepatic TAG levels in n3PUFAs+EX. Insulin sensitivity was improved in EX animals, to a lesser extent in n3PUFA+EX rats, and did not differ between n3PUFA-SED and SED rats. Only the EX group displayed higher complete hepatic fatty acid oxidation (FAO) to CO2 and carnitine palmitoyl transferase-1 activity. EX also lowered hepatic fatty acid synthase protein while both EX and n3PUFA+EX decreased stearoyl CoA desaturase-1 protein. Conclusions. Exercise lowers hepatic steatosis through increased complete hepatic FAO, insulin sensitivity, and reduced expression of de novo fatty acid synthesis proteins while n3PUFAs had no effect

Translational Approach to Examine the Importance of Aerobic Fitness on Nonalcoholic Fatty Liver Disease [abstract]

Comparative Medicine - OneHealth and Comparative Medicine Poster Session.Low cardiorespiratory fitness, independent of physical activity levels, is the best predictor of early mortality and is linked to type 2 diabetes and CVD. In the absence of exercise training, it is believed that genetic inheritance accounts for up to 70% of the variation in intrinsic aerobic fitness. Recent cross-sectional reports in humans also have linked low aerobic fitness with nonalcoholic fatty liver disease (NAFLD). NAFLD, fatty liver not due to alcohol consumption, encompasses a gamut of liver maladaptations and is a primary cause of chronic liver disease and liver-related morbidity and mortality. NAFLD occurs in ~30% of US adults, 75-100% of obese and extremely obese individuals, and is considered the hepatic component of the metabolic syndrome. Despite the recent observations in humans between low fitness and NAFLD, there is a paucity of mechanistic information detailing this link. In order to address this important clinical problem, we have developed an interdisciplinary team across multiple institutions and fields of study and have taken a translational approach, employing both novel whole animal model studies and isolated primary hepatocyte cell culture experiments, to gain mechanistic insight into the human observational studies. We have utilized a novel rat model in which rats are artificially selected over several generations for high and low intrinsic endurance capacity, resulting in high capacity runners (HCR) with high aerobic fitness and low capacity runners (LCR) with significantly lower aerobic fitness (Science, 307:418-20, 2005). These rats display contrasting phenotypes without the influence of exercise training, making them an excellent model to mechanistically assess the role of aerobic fitness on NAFLD. Utilizing this model, we have provided the first mechanistic evidence that the LCR rats have reduced hepatic mitochondrial content and oxidative capacity, increased hepatic de novo lipogenic profiles, and develop hepatic steatosis with progression to greater fibrosis and apoptosis compared to the HCR rats. The LCR rats also are unable to maintain systemic insulin sensitivity following exposure to high-fat feeding. However, since it is impossible to completely eliminate the influence of peripheral factors on liver metabolism, we have subsequently isolated primary hepatocytes from HCR and LCR rats. We have observed a similar phenotype in the primary hepatocytes from LCR animals, with significant reductions in fatty acid oxidation and the inability to maintain insulin signaling in response to lipid exposure compared with HCR hepatocytes. These findings have important clinical implications, as low aerobic fitness due to physical inactivity and/or genetic inheritability may lead to increased susceptibility to NAFLD, and suggest that the clinical measurement of aerobic fitness may serve as a valuable prognostic tool. We are currently conducting a human clinical trial to assess the efficacy of exercise in improving aerobic fitness and reducing NAFLD, and because exercise is the proven method to increase aerobic fitness, it should remain the cornerstone therapy for fatty liver disease

Interdisciplinary Approach to Examine the Effects of Lifestyle Modifications on Nonalcoholic Fatty Liver Disease

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionA critical complication of the obesity epidemic experienced in Westernized societies is nonalcoholic fatty liver disease (NAFLD). NAFLD, fatty liver not due to alcohol consumption, is the most common chronic liver disease and associated with increasing morbidity, mortality, and demand for liver transplantation. NAFLD is a progressive disease with a histological spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and cirrhosis. Approximately one third of all US adults (90 million) have fatty livers, with prevalence rates as high as 75-100% in the obese and morbidly obese. With growing health problems associated with NAFLD, major questions facing research scientists and health care providers are what are the mechanisms responsible for NAFLD development and what is the best treatment strategy. Since drug interventions appear to be only marginally successful, the cornerstone therapy for NAFLD remains lifestyle modifications of exercise and weight loss. However, while recent cross-sectional observations suggest that being more physically active is inversely associated with NAFLD, studies which attempt to identify molecular mechanisms underlying the effects of lifestyle modifications on NAFLD are lacking. To address these clinical questions, we have taken an interdisciplinary approach with collaborations from experts in multiple departments and facilities at the University of Missouri, including Nutrition and Exercise Physiology, Hepatology, Veterinary Biomedical Sciences, and VA investigators. In addition, we have utilized a unique animal model, the hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rat that develops obesity, insulin resistance and overt type 2 diabetes, a model which we liken to overeating, sedentary, obese humans. Through a series of experiments, we found that the natural progression pattern of fatty liver disease in the sedentary OLETF rat closely resembles the human condition (progression from simple hepatic steatosis to hepatocyte ballooning, fibrosis, and inflammation). We also have compelling evidence that hepatic mitochondrial dysfunction is present at an early age and mitochondrial content, function, and mitochondrial health are disrupted with disease progression, suggesting a potential primary event in NAFLD in this animal model. However and perhaps even more important, when OLETF rats are given access to voluntary running wheels and allowed to exercise daily, the initiation and progression of NAFLD is completely prevented. These benefits occur through modification in both peripheral and hepatic factors, including maintenance of glycemic control and enhancement of hepatic mitochondrial content and function. We are currently in the process of translating these very exciting findings in a randomized, human clinical trial examining the impact of different lifestyle modifications in the treatment of NAFLD. Findings from our research group have important public health application, particularly for the 60-80% of Americans who overeat, who are overweight, and who are physically inactive

Rats bred for low and high running capacity display alterations in peripheral tissues and nerves relevant to neuropathy and pain

IntroductionDiet and activity are recognized as modulators of nervous system disease, including pain. Studies of exercise consistently reveal a benefit on pain. This study focused on female rats to understand differences related to metabolic status and peripheral nerve function in females.MethodsHere, we investigated parameters of peripheral nerve function relevant to pain in rats selectively bred for high (high‐capacity runners; HCR) or low endurance exercise capacity (low‐capacity runners; LCR) resulting in divergent intrinsic aerobic capacities and susceptibility for metabolic conditions.ResultsLCR female rats have reduced mechanical sensitivity, higher intraepidermal nerve fiber density and TrkA‐positive epidermal axons, increased numbers of Langerhans and mast cells in cutaneous tissues, and a higher fat content despite similar overall body weights compared to female HCR rats. Sensory and motor nerve conduction velocities, thermal sensitivity, and mRNA expression of selected genes relevant to peripheral sensation were not different.ConclusionsThese results suggest that aerobic capacity and metabolic status influence sensory sensitivity and aspects of inflammation in peripheral tissues that could lead to poor responses to tissue damage and painful stimuli. The LCR and HCR rats should prove useful as models to assess how the metabolic status impacts pain.These results suggest that aerobic capacity and metabolic status influence sensory sensitivity and aspects of inflammation in peripheral tissues that could lead to poor responses to tissue damage and painful stimuli. The LCR and HCR rats should prove useful as models to assess how the metabolic status impacts pain.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139060/1/brb3780.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139060/2/brb3780_am.pd

Rats selectively bred for low aerobic capacity have reduced hepatic mitochondrial oxidative capacity and susceptibility to hepatic steatosis and injury

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65411/1/jphysiol.2009.169060.pd