Exercise Is Medicine: How Do We Implement It?

Exercise is well known to have beneficial effects on various disease states. In this paper, we broadly describe the fundamental concepts that are shared among various disease states, including obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), heart failure (HF), cancer, and psychological well-being, and the beneficial effects of exercise training within these concepts. We highlight issues involved in implementing exercise recommendations and describe the potential impacts and challenges to medical professionals and patients. Problems are identified and discussed with respect to the future roles of professionals in the current built environment with its limited infrastructure to support current physical activity recommendations.

A single bout of cycling exercise induces nucleosome repositioning in the skeletal muscle of lean and overweight/obese individuals.

AIM: To compare the molecular and metabolic effects of a single exercise bout in the skeletal muscle between lean and overweight/obese (Ov/Ob) individuals. MATERIALS AND METHODS: Participants recruited were men, aged 19-30 years, who were either lean (body mass index [BMI] < 25, 18.5-24.1 kg/m2 ; n = 15) or Ov/Ob (BMI ≥ 25, 25.5-36.9 kg/m2 ; n = 15). Four hours after a high-carbohydrate breakfast (7 kcal/kg; 60% carbohydrate, 25% fat, 15% protein), participants performed a cycling exercise (50% VO2 max, expending ~650 kcal). Muscle biopsies and peripheral blood samples were collected 30 minutes before the meal and immediately after exercise. Blood analysis, and muscle acylcarnitine profiles, transcriptomics, and nucleosome mapping by micrococcal nuclease digestion with deep sequencing were performed. RESULTS: A single exercise bout improved blood metabolite profiles in both lean and Ov/Ob individuals. Muscle long-chain acylcarnitines were increased in Ov/Ob compared with lean participants, but were not altered by exercise. A single exercise bout increased the mRNA abundance of genes related to mitochondria and insulin signalling in both lean and Ov/Ob participants. Nucleosome mapping by micrococcal nuclease digestion with deep sequencing revealed that exercise repositioned the -1 nucleosome away from the transcription start site of the PGC1a promoter and of other mitochondrial genes, but did not affect genes related to insulin signalling, in both lean and Ov/Ob participants. CONCLUSION: These data suggest that a single exercise bout induced epigenetic alterations in skeletal muscle in a BMI-independent manner.

Dietary Quercetin Attenuates Adipose Tissue Expansion and Inflammation and Alters Adipocyte Morphology in a Tissue-Specific Manner.

Chronic inflammation in adipose tissue may contribute to depot-specific adipose tissue expansion, leading to obesity and insulin resistance. Dietary supplementation with quercetin or botanical extracts containing quercetin attenuates high fat diet (HFD)-induced obesity and insulin resistance and decreases inflammation. Here, we determined the effects of quercetin and red onion extract (ROE) containing quercetin on subcutaneous (inguinal, IWAT) vs. visceral (epididymal, EWAT) white adipose tissue morphology and inflammation in mice fed low fat, high fat, high fat plus 50 µg/day quercetin or high fat plus ROE containing 50 µg/day quercetin equivalents for 9 weeks. Quercetin and ROE similarly ameliorated HFD-induced increases in adipocyte size and decreases in adipocyte number in IWAT and EWAT. Furthermore, quercetin and ROE induced alterations in adipocyte morphology in IWAT. Quercetin and ROE similarly decreased HFD-induced IWAT inflammation. However, quercetin and red onion differentially affected HFD-induced EWAT inflammation, with quercetin decreasing and REO increasing inflammatory marker gene expression. Quercetin and REO also differentially regulated circulating adipokine levels. These results show that quercetin or botanical extracts containing quercetin induce white adipose tissue remodeling which may occur through inflammatory-related mechanisms.

Short Chain Fatty Acids in the Colon and Peripheral Tissues: A Focus on Butyrate, Colon Cancer, Obesity and Insulin Resistance.

Increased dietary fiber consumption has been associated with many beneficial effects, including amelioration of obesity and insulin resistance. These effects may be due to the increased production of short chain fatty acids, including propionate, acetate and butyrate, during fermentation of the dietary fiber in the colon. Indeed, oral and dietary supplementation of butyrate alone has been shown to prevent high fat-diet induced obesity and insulin resistance. This review focuses on sources of short chain fatty acids, with emphasis on sources of butyrate, mechanisms of fiber and butyrate metabolism in the gut and its protective effects on colon cancer and the peripheral effects of butyrate supplementation in peripheral tissues in the prevention and reversal of obesity and insulin resistance.

Skeletal Muscle Nucleo-Mitochondrial Crosstalk in Obesity and Type 2 Diabetes.

Skeletal muscle mitochondrial dysfunction, evidenced by incomplete beta oxidation and accumulation of fatty acid intermediates in the form of long and medium chain acylcarnitines, may contribute to ectopic lipid deposition and insulin resistance during high fat diet (HFD)-induced obesity. The present review discusses the roles of anterograde and retrograde communication in nucleo-mitochondrial crosstalk that determines skeletal muscle mitochondrial adaptations, specifically alterations in mitochondrial number and function in relation to obesity and insulin resistance. Special emphasis is placed on the effects of high fat diet (HFD) feeding on expression of nuclear-encoded mitochondrial genes (NEMGs) nuclear receptor factor 1 (NRF-1) and 2 (NRF-2) and peroxisome proliferator receptor gamma coactivator 1 alpha (PGC-1α) in the onset and progression of insulin resistance during obesity and how HFD-induced alterations in NEMG expression affect skeletal muscle mitochondrial adaptations in relation to beta oxidation of fatty acids. Finally, the potential ability of acylcarnitines or fatty acid intermediates resulting from mitochondrial beta oxidation to act as retrograde signals in nucleo-mitochondrial crosstalk is reviewed and discussed.

Skeletal Muscle PGC1α -1 Nucleosome Position and -260 nt DNA Methylation Determine Exercise Response and Prevent Ectopic Lipid Accumulation in Men.

Endurance exercise has been shown to improve lipid oxidation and increase mitochondrial content in skeletal muscle, two features that have shown dependence on increased expression of the peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α). It is also hypothesized that exercise-related alterations in PGC1α expression occur through epigenetic regulation of nucleosome positioning in association with differential DNA methylation status within the PGC1α promoter. In this study, we show that when primary human myotubes from obese patients with type 2 diabetes are exposed to lipolytic stimulus (palmitate, forskolin, inomycin) in vitro, nucleosome occupancy surrounding the -260 nucleotide (nt) region, a known regulatory DNA methylation site, is reduced. This finding is reproduced in vivo in the vastus lateralis from 11 healthy males after a single, long endurance exercise bout in which participants expended 650 kcal. Additionally, we show a significant positive correlation between fold change of PGC1α messenger RNA expression and -1 nucleosome repositioning away from the -260 nt methylation site in skeletal muscle tissue following exercise. Finally, we found that when exercise participants are divided into high and low responders based on the -260 nt methylation status, the -1 nucleosome is repositioned away from the regulatory -260 nt methylation site in high responders, those exhibiting a significant decrease in -260 nt methylation, but not in low responders. Additionally, high but not low responders showed a significant decrease in intramyocellular lipid content after exercise. These findings suggest a potential target for epigenetic modification of the PGC1α promoter to stimulate the therapeutic effects of endurance exercise in skeletal muscle.

Quercetin and Quercetin-Rich Red Onion Extract Alter Pgc-1α Promoter Methylation and Splice Variant Expression.

Pgc-1α and its various isoforms may play a role in determining skeletal muscle mitochondrial adaptations in response to diet. 8 wks of dietary supplementation with the flavonoid quercetin (Q) or red onion extract (ROE) in a high fat diet (HFD) ameliorates HFD-induced obesity and insulin resistance in C57BL/J mice while upregulating Pgc-1α and increasing skeletal muscle mitochondrial number and function. Here, mice were fed a low fat (LF), high fat (HF), high fat plus quercetin (HF + Q), or high fat plus red onion extract (HF + RO) diet for 9 wks and skeletal muscle Pgc-1α isoform expression and DNA methylation were determined. Quantification of various Pgc-1α isoforms, including isoforms Pgc-1α-a, Pgc-1α-b, Pgc-1α-c, Pgc-1α4, total NT-Pgc-1α, and FL-Pgc-1α, showed that only total NT-Pgc-1α expression was increased in LF, HF + Q, and HF + RO compared to HF. Furthermore, Q supplementation decreased Pgc-1α-a expression compared to LF and HF, and ROE decreased Pgc-1α-a expression compared to LF. FL-Pgc-1α was decreased in HF + Q and HF + RO compared to LF and HF. HF exhibited hypermethylation at the -260 nucleotide (nt) in the Pgc-1α promoter. Q and ROE prevented HFD-induced hypermethylation. -260 nt methylation levels were associated with NT-Pgc-1α expression only. Pgc-1α isoform expression may be epigenetically regulated by Q and ROE through DNA methylation.

Emerging Relationships Between Vitamin D Status, Physical Activity Habits, and Immune Indices in College-Aged Females.

It has been determined that individuals who are regularly physically active have more favorable inflammatory profiles; less is known about how vitamin D levels can impact inflammation. This study explored the relationship between inflammatory indices in physically active (PA) and not physically active (NPA) individuals with 25-hydroxyvitamin D (25OHD) concentrations either above or below optimal concentrations. All female subjects (n = 63, age 19 - 35 years) were evaluated for body composition, maximal aerobic capacity (VO2peak), and anaerobic power (Wingate). Blood samples were analyzed for 25OHD and C-reactive protein (CRP), stimulated with lipopolysaccharide (LPS) and assessed for interleukin-6 (IL-6) production, and used for flow cytometric analysis. PA (n = 30) had higher 25OHD levels (45.2 ± 2.7 vs. 17.05 ± 1.4 ng / mL; p = 0.015), higher VO2peak (p < 0.0001), lower body weight (p = 0.039) and lower estimated percent body fat (p = 0.011) compared to NPA (n = 33). PA also had lower LPS-stimulated IL-6 production compared to NPA (p = 0.0163), although there were no differences between resting CRP concentrations. NPA with optimal 25OHD had fewer total monocytes, CD14+CD16-cells, CD14+CD16+ cells, and decreased TLR4 expression on CD14+CD16+ cells compared to NPA with suboptimal 25OHD (< 32 ng / mL). In summary, regular physical activity was associated with higher serum 25OHD, healthier measures of body composition, and reduced stimulated IL-6 production. However, optimal vitamin D status was not associated with anti-inflammatory benefits beyond those which are provided by regular physical activity.

Regulation of Brown and White Adipocyte Transcriptome by the Transcriptional Coactivator NT-PGC-1α.

The ß3-adrenergic receptor (AR) signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The ß3-AR signaling highly induces the expression of transcriptional coactivator PGC-1α and its splice variant N-terminal (NT)-PGC-1α, which in turn activate the transcription program of adaptive thermogenesis by co-activating a number of transcription factors. We previously reported that NT-PGC-1α is able to increase mitochondrial number and activity in cultured brown adipocytes by promoting the expression of mitochondrial and thermogenic genes. In the present study, we performed genome-wide profiling of NT-PGC-1α-responsive genes in brown adipocytes to identify genes potentially regulated by NT-PGC-1α. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1α are highly enriched in mitochondrial pathways including fatty acid transport and ß-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1α in the enhancement of mitochondrial function. Moreover, canonical pathway analysis of NT-PGC-1α-responsive genes identified several metabolic pathways including glycolysis and fatty acid synthesis. In order to validate the identified genes in vivo, we utilized the FL-PGC-1α-/- mouse that is deficient in full-length PGC-1α (FL-PGC-1α) but expresses a slightly shorter and functionally equivalent form of NT-PGC-1α (NT-PGC-1α254). The ß3-AR-induced increase of NT-PGC-1α254 in FL-PGC-1α-/- brown and white adipose tissue was closely associated with elevated expression of genes involved in thermogenesis, mitochondrial oxidative metabolism, glycolysis and fatty acid synthesis. Increased adipose tissue thermogenesis by ß3-AR activation resulted in attenuation of adipose tissue expansion in FL-PGC-1α-/- adipose tissue under the high-fat diet condition. Together, the data strengthen our previous findings that NT-PGC-1α regulates mitochondrial genes involved in thermogenesis and oxidative metabolism in brown and white adipocytes and further suggest that NT-PGC-1α regulates a broad spectrum of genes to meet cellular needs for adaptive thermogenesis.

Hepatic autophagy contributes to the metabolic response to dietary protein restriction.

Autophagy is an essential cellular response which acts to release stored cellular substrates during nutrient restriction, and particularly plays a key role in the cellular response to amino acid restriction. However, there has been limited work testing whether the induction of autophagy is required for adaptive metabolic responses to dietary protein restriction in the whole animal. Here, we found that moderate dietary protein restriction led to a series of metabolic changes in rats, including increases in food intake and energy expenditure, the downregulation of hepatic fatty acid synthesis gene expression and reduced markers of hepatic mitochondrial number. Importantly, these effects were also associated with an induction of hepatic autophagy. To determine if the induction of autophagy contributes to these metabolic effects, we tested the metabolic response to dietary protein restriction in BCL2-AAA mice, which bear a genetic mutation that impairs autophagy induction. Interestingly, BCL2-AAA mice exhibit exaggerated responses in terms of both food intake and energy expenditure, whereas the effects of protein restriction on hepatic metabolism were significantly blunted. These data demonstrate that restriction of dietary protein is sufficient to trigger hepatic autophagy, and that disruption of autophagy significantly alters both hepatic and whole animal metabolic response to dietary protein restriction.

Sodium butyrate epigenetically modulates high-fat diet-induced skeletal muscle mitochondrial adaptation, obesity and insulin resistance through nucleosome positioning.

BACKGROUND AND PURPOSE: Sodium butyrate (NaB), an epigenetic modifier, is effective in promoting insulin sensitivity. The specific genomic loci and mechanisms underlying epigenetically induced obesity and insulin resistance and the targets of NaB are not fully understood. EXPERIMENTAL APPROACH: The anti-diabetic and anti-obesity effects of NaB treatment were measured by comparing phenotypes and physiologies of C57BL/6J mice fed a low-fat diet (LF), high-fat diet (HF) or high-fat diet plus NaB (HF + NaB) for 10 weeks. We determined a possible mechanism of NaB action through induction of beneficial skeletal muscle mitochondrial adaptations and applied microccocal nuclease digestion with sequencing (MNase-seq) to assess whole genome differences in nucleosome occupancy or positioning and to identify associated epigenetic targets of NaB. KEY RESULTS: NaB prevented HF diet-induced increases in body weight and adiposity without altering food intake or energy expenditure, improved insulin sensitivity as measured by glucose and insulin tolerance tests, and decreased respiratory exchange ratio. In skeletal muscle, NaB increased the percentage of type 1 fibres, improved acylcarnitine profiles as measured by metabolomics and produced a chromatin structure, determined by MNase-seq, similar to that seen in LF. Targeted analysis of representative nuclear-encoded mitochondrial genes showed specific repositioning of the -1 nucleosome in association with altered gene expression. CONCLUSIONS AND IMPLICATIONS: NaB treatment may be an effective pharmacological approach for type 2 diabetes and obesity by inducing -1 nucleosome repositioning within nuclear-encoded mitochondrial genes, causing skeletal muscle mitochondrial adaptations that result in more complete ß-oxidation and a lean, insulin sensitive phenotype.

P65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice.

NF-κB induces transcriptional expression of proinflammatory genes and antiapoptotic genes. The two activities of NF-κB remain to be characterized in the mechanism of chronic inflammation in obesity. To address this issue, we inactivated NF-κB in adipose tissue by knocking out p65 (RelA) in mice (F-p65-KO) and examined the inflammation in lean and obese conditions. In the lean condition, KO mice exhibited a reduced inflammation in adipose tissue with a decrease in macrophage infiltration, M1 polarization, and proinflammatory cytokine expression. In the obese condition, KO mice had elevated inflammation with more macrophage infiltration, M1 polarization, and cytokine expression. In the mechanism of enhanced inflammation, adipocytes and macrophages exhibited an increase in cellular apoptosis, which was observed with more formation of crown-like structures (CLS) in fat tissue of KO mice. Body weight, glucose metabolism, and insulin sensitivity were not significantly altered in KO mice under the lean and obese conditions. A modest but significant reduction in body fat mass was observed in KO mice on HFD with an elevation in energy expenditure. The data suggest that in the control of adipose inflammation, NF-κB exhibits different activities in the lean vs. obese condition. NF-κB is required for expression of proinflammatory genes in the lean but not in the obese condition. NF-κB is required for inhibition of apoptosis in the obese condition, in which proinflammation is enhanced by NF-κB inactivation.

A Review of Mitochondrial-derived Fatty Acids in Epigenetic Regulation of Obesity and Type 2 Diabetes.

Type 2 diabetes, the leading metabolic disease, is characterized by insulin resistance and is associated with obesity. The onset of type 2 diabetes is largely due to environmental inputs, such as high dietary fat content and decreased levels of exercise. Insulin resistance resulting from high fat diet is associated with skeletal muscle mitochondrial dysfunction, leading to alterations in lipid accumulation and specific species of intracellular fatty acids; whereas, exercise training augments insulin resistance while improving skeletal muscle mitochondrial function and producing beneficial fatty acid profiles. Additionally, high fat diets and exercise alter epigenetic modifications, including DNA methylation and histone acetylation, to produce differences in metabolic gene expression that are associated with insulin resistance and sensitivity, respectively. Recent evidence suggests that short chain fatty acids that act as histone deacetylase inhibitors prevent and ameliorate obesity and insulin resistance. Here, we discuss the potential of mitochondrial-derived fatty acids, especially short chain fatty acids, to epigenetically regulate obesity and type 2 diabetes.

FGF21 is an endocrine signal of protein restriction.

Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. LP-induced increases in FGF21 were associated with increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the liver, and both baseline and LP-induced serum FGF21 levels were reduced in mice lacking the eIF2α kinase general control nonderepressible 2 (GCN2). Finally, while protein restriction altered food intake, energy expenditure, and body weight gain in WT mice, FGF21-deficient animals did not exhibit these changes in response to a LP diet. These and other data demonstrate that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake.

Leucine acts in the brain to suppress food intake but does not function as a physiological signal of low dietary protein.

Intracerebroventricular injections of leucine are sufficient to suppress food intake, but it remains unclear whether brain leucine signaling represents a physiological signal of protein balance. We tested whether variations in dietary and circulating levels of leucine, or all three branched-chain amino acids (BCAAs), contribute to the detection of reduced dietary protein. Of the essential amino acids (EAAs) tested, only intracerebroventricular injection of leucine (10 µg) was sufficient to suppress food intake. Isocaloric low- (9% protein energy; LP) or normal- (18% protein energy) protein diets induced a divergence in food intake, with an increased consumption of LP beginning on day 2 and persisting throughout the study (P < 0.05). Circulating BCAA levels were reduced the day after LP diet exposure, but levels subsequently increased and normalized by day 4, despite persistent hyperphagia. Brain BCAA levels as measured by microdialysis on day 2 of diet exposure were reduced in LP rats, but this effect was most prominent postprandially. Despite these diet-induced changes in BCAA levels, reducing dietary leucine or total BCAAs independently from total protein was neither necessary nor sufficient to induce hyperphagia, while chronic infusion of EAAs into the brain of LP rats failed to consistently block LP-induced hyperphagia. Collectively, these data suggest that circulating BCAAs are transiently reduced by dietary protein restriction, but variations in dietary or brain BCAAs alone do not explain the hyperphagia induced by a low-protein diet.

Dietary quercetin supplementation in mice increases skeletal muscle PGC1α expression, improves mitochondrial function and attenuates insulin resistance in a time-specific manner.

AIMS/HYPOTHESIS: High fat diet (HFD)-induced insulin resistance (IR) is partially characterized by reduced skeletal muscle mitochondrial function and peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1α) expression. Our previous study showed that a high dose of the bioflavonoid quercetin exacerbated HFD-induced IR; yet, others have demonstrated that quercetin improves insulin sensitivity. The aim of this study was to investigate whether differing doses of quercetin act in a time-dependent manner to attenuate HFD-induced IR in association with improved skeletal muscle mitochondrial function and PGC1α expression. METHODS: C57BL/6J mice were fed HFD for 3 or 8 wks, with or without a low (50 ug/day; HF+50Q) or high (600 ug/day, HF+600Q) dose of quercetin. Whole body and metabolic phenotypes and insulin sensitivity were assessed. Skeletal muscle metabolomic analysis of acylcarnitines and PGC1α mRNA expression via qRT-PCR were measured. RESULTS: Quercetin at 50 ug/day for 8 wk attenuated HFD-induced increases in fat mass, body weight and IR and increased PGC1α expression, whereas 600 ug/day of quercetin exacerbated fat mass accumulation without altering body weight, IR or PGC1α. PGC1α expression correlated with acylcarnitine levels similarly in HF and HF+600Q; these correlations were not present in HF+50Q. At both time points, energy expenditure increased in HF+50Q and decreased in HF+600Q, independent of PGC1α and IR. CONCLUSIONS/INTERPRETATION: Chronic dietary quercetin supplementation at low but not higher dose ameliorates the development of diet-induced IR while increasing PGC1α expression in muscle, suggesting that skeletal muscle may be an important target for the insulin-sensitizing effects of a low dose of quercetin.

Vitamin D status, body composition, and fitness measures in college-aged students.

Low vitamin D, commonly assessed as serum 25-hydroxyvitamin D (25OHD), is associated with the development of many age-related chronic diseases. A positive relationship exists between elevated 25OHD and muscle synthesis, strength, power, and decreased body fat in elderly individuals. However, these findings have not been consistently reported in younger healthy populations. The purpose of this study was to investigate the relationship between 25OHD and measures of body size, composition, metabolism, and physical fitness in a young physically active population. Thirty-nine subjects (20 men, 19 women; aged 23 ± 0.7 years) reported 6 times for testing. Blood was collected to determine 25OHD. Primary outcomes included the following: body mass index (BMI) and percent body fat (dual x-ray absorptiometry); resting metabolic rate; maximal oxygen uptake (V[Combining Dot Above]O2max); power output (Wingate); and muscular strength (8 repetition maximum for bench press, upright row, and leg extension and flexion exercises). Our analysis included all participants, and subgroup analyses for individuals with suboptimal 25OHD concentration below 35 ng·mL ("low"; n = 20, 25.97 ± 1.97 ng·mL) or equal to and above 35 ng·mL ("high"; n = 19, 44.15 ± 2.17 ng·mL). Twenty subjects in this study had serum levels of 25OHD below 35 ng·mL. There was a significant positive relationship between V[Combining Dot Above]O2max and serum 25OHD and a negative relationship between BMI and serum 25OHD. These data suggest that vitamin D deficiency is prevalent even in a young physically active population in the southern United States and that there was a positive relationship between a measure of cardiovascular fitness and serum 25OHD, and a negative relationship between serum 25OHD and BMI.

PGC1α -1 Nucleosome Position and Splice Variant Expression and Cardiovascular Disease Risk in Overweight and Obese Individuals.

PGC1α, a transcriptional coactivator, interacts with PPARs and others to regulate skeletal muscle metabolism. PGC1α undergoes splicing to produce several mRNA variants, with the NTPGC1α variant having a similar biological function to the full length PGC1α (FLPGC1α). CVD is associated with obesity and T2D and a lower percentage of type 1 oxidative fibers and impaired mitochondrial function in skeletal muscle, characteristics determined by PGC1α expression. PGC1α expression is epigenetically regulated in skeletal muscle to determine mitochondrial adaptations, and epigenetic modifications may regulate mRNA splicing. We report in this paper that skeletal muscle PGC1α -1 nucleosome (-1N) position is associated with splice variant NTPGC1α but not FLPGC1α expression. Division of participants based on the -1N position revealed that those individuals with a -1N phased further upstream from the transcriptional start site (UP) expressed lower levels of NTPGC1α than those with the -1N more proximal to TSS (DN). UP showed an increase in body fat percentage and serum total and LDL cholesterol. These findings suggest that the -1N may be a potential epigenetic regulator of NTPGC1α splice variant expression, and -1N position and NTPGC1α variant expression in skeletal muscle are linked to CVD risk. This trial is registered with clinicaltrials.gov, identifier NCT00458133.

Melanocortin receptor expression is associated with reduced CRP in response to resistance training.

The existing paradigm of exercise-induced decreases in chronic inflammation focuses on the expression of inflammatory receptors on systemic monocytes in response to exercise training, with the role of anti-inflammatory receptors largely ignored. Our recent preliminary studies indicate that the anti-inflammatory melanocortin receptors (MCRs) may play a role in modulating exercise-induced decreases in chronic inflammation. Here, we present a study designed to determine the effect of intense, resistance exercise training on systemic monocyte MCR expression. Because low-grade chronic inflammation is associated with elevated cardiometabolic risk in healthy populations and exercise decreases chronic inflammation, we investigated the associations between systemic monocyte cell surface expression of MCRs and inflammatory markers as a possible mechanism for the beneficial anti-inflammatory effects of resistance training. To this end, the present study includes 40 adults (aged 19-27 yr) and implements a 12-wk periodized, intensive resistance training intervention. Melanocortin 1 and 3 receptor expression on systemic monocytes and inflammatory markers, including C-reactive protein (CRP), interleukin (IL)-6, IL-1ß, and IL-10, were measured before and after the intervention. Resistance training significantly altered MCR systemic monocyte cell surface expression, had no chronic effects on IL-6, IL-1ß, or IL-10 expression, but significantly decreased CRP levels from a moderate to a low cardiovascular disease risk category. More specifically, decreased melanocortin 3 receptor expression significantly correlated with decreased CRP, independent of changes in adiposity. These data suggest that the observed responses in MCR expression and decreases in cardiovascular disease risk in response to resistance training represent an important anti-inflammatory mechanism in regulating exercise-induced decreases in chronic inflammation that occur independent of chronic changes in systemic cytokines.

Homeostatic regulation of protein intake: in search of a mechanism.

Free-living organisms must procure adequate nutrition by negotiating an environment in which both the quality and quantity of food vary markedly. Recent decades have seen marked progress in our understanding of neural regulation of feeding behavior. However, this progress has occurred largely in the context of energy intake, despite the fact that food intake is influenced by more than just the energy content of the diet. A large number of behavioral studies indicate that both the quantity and quality of dietary protein can markedly influence food intake. High-protein diets tend to reduce intake, low-protein diets tend to increase intake, and rodent models seem to self-select between diets in order to meet protein requirements and avoid diets that are imbalanced in amino acids. Recent work suggests that the amino acid leucine regulates food intake by altering mTOR and AMPK signaling in the hypothalamus, while activation of GCN2 within the anterior piriform cortex contributes to the detection and avoidance of amino acid-imbalanced diets. This review focuses on the role that these and other signaling systems may play in mediating the homeostatic regulation of protein balance, and in doing so, highlights our lack of knowledge regarding the physiological and neurobiological mechanisms that might underpin such a regulatory phenomenon.