A Novel Endocrine Role for the BAT-Released Lipokine 12,13-diHOME to Mediate Cardiac Function.

BACKGROUND: Brown adipose tissue (BAT) is an important tissue for thermogenesis, making it a potential target to decrease the risks of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified BAT as an endocrine organ. Although BAT has been implicated to be protective in cardiovascular disease, to this point there are no studies that identify a direct role for BAT to mediate cardiac function. METHODS: To determine the role of BAT on cardiac function, we utilized a model of BAT transplantation. We then performed lipidomics and identified an increase in the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). We utilized a mouse model with sustained overexpression of 12,13-diHOME and investigated the role of 12,13-diHOME in a nitric oxide synthase type 1 deficient (NOS1-/-) mouse and in isolated cardiomyocytes to determine effects on function and respiration. We also investigated 12,13-diHOME in a cohort of human patients with heart disease. RESULTS: Here, we determined that transplantation of BAT (+BAT) improves cardiac function via the release of the lipokine 12,13-diHOME. Sustained overexpression of 12,13-diHOME using tissue nanotransfection negated the deleterious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13-diHOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13-diHOME increased mitochondrial respiration. The effects of 12,13-diHOME were absent in NOS1-/- mice and cardiomyocytes. We also provide the first evidence that 12,13-diHOME is decreased in human patients with heart disease. CONCLUSIONS: Our results identify an endocrine role for BAT to enhance cardiac function that is mediated by regulation of calcium cycling via 12,13-diHOME and NOS1.

Brown adipose tissue prevents glucose intolerance and cardiac remodeling in high-fat-fed mice after a mild myocardial infarction.

BACKGROUND: Obesity increases the risk of developing impaired glucose tolerance (IGT) and type 2 diabetes (T2D) after myocardial infarction (MI). Brown adipose tissue (BAT) is important to combat obesity and T2D, and increasing BAT mass by transplantation improves glucose metabolism and cardiac function. The objective of this study was to determine if BAT had a protective effect on glucose tolerance and cardiac function in high-fat diet (HFD) fed mice subjected to a mild MI. METHODS: Male C57BL/6 mice were fed a HFD for eight weeks and then divided into Sham (Sham-operated) and +BAT (mice receiving 0.1 g BAT into their visceral cavity). Sixteen weeks post-transplantation, mice were further subdivided into ±MI (Sham; Sham-MI; +BAT; +BAT-MI) and maintained on a HFD. Cardiac (echocardiography) and metabolic function (glucose and insulin tolerance tests, body composition and exercise tolerance) were assessed throughout 22 weeks post-MI. Quantitative PCR (qPCR) was performed to determine the expression of genes related to metabolic function of perigonadal adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), liver, heart, tibialis anterior skeletal muscle (TA); and BAT. RESULTS: +BAT prevented the increase in left ventricle mass (LVM) and exercise intolerance in response to MI. Similar to what is observed in humans, Sham-MI mice developed IGT post-MI, but this was negated in +BAT-MI mice. IGT was independent of changes in body composition. Genes involved in inflammation, insulin resistance, and metabolism were significantly altered in pgWAT, scWAT, and liver in Sham-MI mice compared to all other groups. CONCLUSIONS: BAT transplantation prevents IGT, the increase in LVM, and exercise intolerance following MI. MI alters the expression of several metabolic-related genes in WAT and liver in Sham-MI mice, suggesting that these tissues may contribute to the impaired metabolic response. Increasing BAT may be an important intervention to prevent the development of IGT or T2D and cardiac remodeling in obese patients post-MI.

Phospho-ablation of cardiac sodium channel Nav1.5 mitigates susceptibility to atrial fibrillation and improves glucose homeostasis under conditions of diet-induced obesity.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia, with growing evidence identifying obesity as an important risk factor for the development of AF. Although defective atrial myocyte excitability due to stress-induced remodeling of ion channels is commonly observed in the setting of AF, little is known about the mechanistic link between obesity and AF. Recent studies have identified increased cardiac late sodium current (INa,L) downstream of calmodulin-dependent kinase II (CaMKII) activation as an important driver of AF susceptibility. METHODS: Here, we investigated a possible role for CaMKII-dependent INa,L in obesity-induced AF using wild-type (WT) and whole-body knock-in mice that ablates phosphorylation of the Nav1.5 sodium channel and prevents augmentation of the late sodium current (S571A; SA mice). RESULTS: A high-fat diet (HFD) increased susceptibility to arrhythmias in WT mice, while SA mice were protected from this effect. Unexpectedly, SA mice had improved glucose homeostasis and decreased body weight compared to WT mice. However, SA mice also had reduced food consumption compared to WT mice. Controlling for food consumption through pair feeding of WT and SA mice abrogated differences in weight gain and AF inducibility, but not atrial fibrosis, premature atrial contractions or metabolic capacity. CONCLUSIONS: These data demonstrate a novel role for CaMKII-dependent regulation of Nav1.5 in mediating susceptibility to arrhythmias and whole-body metabolism under conditions of diet-induced obesity.

A Low Protein Diet during Gestation and Lactation Increases Hepatic Lipid Accumulation through Autophagy and Histone Deacetylase.

The present study examined the mechanism of a low protein (LP) diet on hepatic lipid metabolism during gestation and lactation. Timed-pregnant Sprague-Dawley rats were fed a control or an LP diet during gestation and lactation. LP dams had increased hepatic triglyceride accumulation and significantly higher aspartate/alanine transaminase ratio, accompanied by a decrease in circulating very low-density/low-density lipoprotein ratio. LC3B (Microtubule Associated Protein 1 Light Chain 3 Beta) expression was stimulated in LP dams along with increased histone acetylation. LP diet-induced co-localization of the LC3 binding motif-interacting proteins APOB or MTTP with LC3B, suggesting autophagic degradation. HDAC3 is found necessary to prevent lipid accumulation in response to amino acid deprivation in HepG2 cells. LC3B-mediated APOB protein degradation is related to increases in lipid accumulation. Conclusion: HDAC3 regulated LC3B-induced lipid accumulation potentially through autophagic degradation of APOB and MTTP in response to amino acid limitation caused by a low protein diet.

Effects of obesity and exercise on colon cancer induction and hematopoiesis in mice.

Obesity-induced inflammation is associated with increased risk for colorectal cancer (CRC). The role of diet and exercise in modulating increased CRC risk in obesity and the potential role of altered hematopoiesis as a contributor to these effects remain unknown. The purpose of this study was to examine how weight loss induced during CRC induction with or without exercise alters CRC initiation and its relationship to altered hematopoiesis. Mice consumed either a control (CON) or a high-fat diet to induce obesity. All mice were then placed on the control diet during CRC induction with azoxymethane (AOM). Following AOM injection, mice originally on the high-fat diet were randomized into sedentary (HF-SED) or exercise trained (HF-EX) conditions. At euthanasia, body weight and fat mass were similar among all three groups ( P < 0.05). Compared with CON and HF-EX, HF-SED developed increased content of preneoplastic lesions ( P < 0.05), and HF-SED had significantly increased markers of colon inflammation compared with CON. Compared with both CON and HF-EX, HF-SED had decreased content of short-term hematopoietic stem cells and increased content of common myeloid progenitor cells (both P < 0.05). Similarly, HF-SED had increased bone marrow adiposity compared with CON and HF-EX ( P < 0.05), and proteomics analysis revealed an increased marker of bone marrow inflammation in HF-SED compared with CON and HF-EX. Our results suggest that the early removal of a high-fat diet reduces CRC incidence when combined with an exercise training intervention. This reduction in risk was related to lower colon inflammation with anti-inflammatory changes in hematopoiesis induced by exercise.

Perinatal High-Fat Diet and Bisphenol A: Effects on Behavior and Gene Expression in the Medial Prefrontal Cortex.

Both high-fat diets (HFD) and bisphenol A (BPA), an environmental endocrine disruptor, are prevalent in industrialized societies. Previous studies have detected separate effects of BPA and HFD; however, none have assessed possible interactive effects. Here, pregnant dams consumed 0, 40, or 400 µg BPA/kg/day and were fed either a control (CON; 15.8% kcal fat) or HFD (45% kcal fat) from gestational day 2 through parturition. The pups were individually dosed with BPA from postnatal days (P) 1-10, while the dams continued to consume one of the two diets. Maternal behavior increased with the HFD while the offspring's periadolescent social play decreased with BPA, but no interactive effects were observed. Neither HFD nor BPA exposure changed performance on a social recognition task, and only BPA had an effect on the elevated plus maze. BPA increased several cytokines in the medial prefrontal cortex (mPFC) of P10 males but not females. Expression of several genes related to hormone synthesis and receptors, inflammation, oxidative stress, and apoptosis in the mPFC on P10 and P90 were altered due to BPA and/or HFD exposure with rare interactive effects. BPA resulted in an increase in the gene expression of Esr1 in the mPFC of females on both P10 and P90. Epigenetic analysis on P90 did not show a change in methylation or in the levels of pre-mRNA or microRNA. Thus, perinatal BPA and HFD have separate effects but rarely interact.

Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation.

Aging is associated with low-grade inflammation that increases the risk of infection and disease, yet the underlying mechanisms remain unclear. Gut microbiota composition shifts with age, harboring microbes with varied immunogenic capacities. We hypothesized the gut microbiota acts as an active driver of low-grade inflammation during aging. Microbiome patterns in aged mice strongly associated with signs of bacterial-induced barrier disruption and immune infiltration, including marked increased levels of circulating lipopolysaccharide (LPS)-binding protein (LBP) and colonic calprotectin. Ex vivo immunogenicity assays revealed that both colonic contents and mucosa of aged mice harbored increased capacity to activate toll-like receptor 4 (TLR4) whereas TLR5 signaling was unchanged. We found patterns of elevated innate inflammatory signaling (colonic Il6, Tnf, and Tlr4) and endotoxemia (circulating LBP) in young germ-free mice after 4 weeks of colonization with intestinal contents from aged mice compared with young counterparts, thus providing a direct link between aging-induced shifts in microbiota immunogenicity and host inflammation. Additionally, we discovered that the gut microbiota of aged mice exhibited unique responses to a broad-spectrum antibiotic challenge (Abx), with sustained elevation in Escherichia (Proteobacteria) and altered TLR5 immunogenicity 7 days post-Abx cessation. Together, these data indicate that old age results in a gut microbiota that differentially acts on TLR signaling pathways of the innate immune system. We found that these age-associated microbiota immunogenic signatures are less resilient to challenge and strongly linked to host inflammatory status. Gut microbiota immunogenic signatures should be thus considered as critical factors in mediating chronic inflammatory diseases disproportionally impacting older populations.

Chronic exercise improves hepatic acylcarnitine handling.

Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance trained human subjects compared to sedentary controls, and this is correlated with elevated cardiorespiratory fitness and reduced adiposity. In mice, exercise reduced serum AC and increased liver AC, and this was accompanied by a marked increase in expression of genes involved in hepatic AC metabolism and mitochondrial ß-oxidation. Primary hepatocytes from high-fat fed, exercise trained mice had increased basal respiration compared to hepatocytes from high-fat fed sedentary mice, which may be attributed to increased Ca2+ cycling and lipid uptake into mitochondria. The addition of specific medium- and long-chain AC to sedentary hepatocytes increased mitochondrial respiration, mirroring the exercise phenotype. These data indicate that AC redistribution is an exercise-induced mechanism to improve hepatic function and metabolism.

Transplantation of committed pre-adipocytes from brown adipose tissue improves whole-body glucose homeostasis.

Obesity and its co-morbidities including type 2 diabetes are increasing at epidemic rates in the U.S. and worldwide. Brown adipose tissue (BAT) is a potential therapeutic to combat obesity and type 2 diabetes. Increasing BAT mass by transplantation improves metabolic health in rodents, but its clinical translation remains a challenge. Here, we investigated if transplantation of 2-4 million differentiated brown pre-adipocytes from mouse BAT stromal fraction (SVF) or human pluripotent stem cells (hPSCs) could improve metabolic health. Transplantation of differentiated brown pre-adipocytes, termed "committed pre-adipocytes" from BAT SVF from mice or derived from hPSCs improves glucose homeostasis and insulin sensitivity in recipient mice under conditions of diet-induced obesity, and this improvement is mediated through the collaborative actions of the liver transcriptome, tissue AKT signaling, and FGF21. These data demonstrate that transplantation of a small number of brown adipocytes has significant long-term translational and therapeutic potential to improve glucose metabolism.

Cooked common beans (Phaseolus vulgaris) protect against ß-cell damage in streptozotocin-induced diabetic rats.

Diabetes is a disease characterized by a hyperglycemic stage that leads to a chronic inflammatory state. We evaluated the in vivo effect of a diet supplemented with 25 % cooked black bean cultivar Negro 8025 (N8025) flour in streptozotocin-induced diabetic rats. The effect was assessed before (preventive-treatment) and after (treatment) the onset of diabetes. There is a significant decrease of total phenolic, tannins and anthocyanins content after cooking, and the concentration of most of the single phenols analyzed are only slightly decreased. The treatment group showed a significant reduction of glucose (22.8 %), triglycerides (21.9 %), total cholesterol (29.9 %) and LDL (56.1 %) that correlates with a protection of pancreatic ß-cells. The diet with N8025 flour before the induction of diabetes did not exert a protective effect (glucose levels are similar to the diabetic control) but they have low levels of total cholesterol (47.5 %) and LDL (56.1 %). The preventive-treatment group did not inhibit the increase of TNF-α and IL-1ß, whereas the treatment group did, compared to the diabetic control. Therefore, N8025 bean supplementation can be recommended to control diabetes.

Exercise training modifies xenometabolites in gut and circulation of lean and obese adults.

Regular, moderate exercise modifies the gut microbiome and contributes to human metabolic and immune health. The microbiome may exert influence on host physiology through the microbial production and modification of metabolites (xenometabolites); however, this has not been extensively explored. We hypothesized that 6 weeks of supervised, aerobic exercise 3×/week (60%-75% heart rate reserve [HRR], 30-60 min) in previously sedentary, lean (n = 14) and obese (n = 10) adults would modify both the fecal and serum xenometabolome. Serum and fecal samples were collected pre- and post-6 week intervention and analyzed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Linear mixed models (LMMs) identified multiple fecal and serum xenometabolites responsive to exercise training. Further cluster and pathway analysis revealed that the most prominent xenometabolic shifts occurred within aromatic amino acid (ArAA) metabolic pathways. Fecal and serum ArAA derivatives correlated with body composition (lean mass), markers of insulin sensitivity (insulin, HOMA-IR) and cardiorespiratory fitness ( V ̇ O 2 max $$ \dot{\mathrm{V}}{\mathrm{O}}_{2\max } $$ ), both at baseline and in response to exercise training. Two serum aromatic microbial-derived amino acid metabolites that were upregulated following the exercise intervention, indole-3-lactic acid (ILA: fold change: 1.2, FDR p < 0.05) and 4-hydroxyphenyllactic acid (4-HPLA: fold change: 1.3, FDR p < 0.05), share metabolic pathways within the microbiota and were associated with body composition and markers of insulin sensitivity at baseline and in response to training. These data provide evidence of physiologically relevant shifts in microbial metabolism that occur in response to exercise training, and reinforce the view that host metabolic health influences gut microbiota population and function. Future studies should consider the microbiome and xenometabolome when investigating the health benefits of exercise.

Consumption of cricket (Acheta domesticus) flour decreases insulin resistance and fat accumulation in rats fed with high-fat and -fructose diet.

The consumption of cricket (Acheta domesticus, AD) has recently increased due to its high nutritional and bioactive compound contents. However, limited studies have explored the beneficial effects of AD consumption. Therefore, we aimed to evaluate the protective effect of a diet supplemented with AD flour on obesity control and its complications in an in vivo model. The chemical profiling of the AD showed an important protein content, chitin, and polyunsaturated fatty acids contents. For the in vivo study, a high-fructose and saturated fat diet (HFFD) was supplemented with AD (4% and 8%). The 8% AD supplementation reduced body weight gain (19%) and serum triglycerides (37%) in HFFD-fed rats. These benefits were related to a greater lipid excretion in feces (97%) and the partial inhibition of pancreatic lipase in vitro by the aqueous extract and the hydrolyzed proteins obtained from AD. Additionally, the 8% AD supplementation improved insulin resistance measured by the HOMA index (61%). Thus, 8% AD supplementation to HFFD-fed rats was effective in preventing obesity, dyslipidemia, and insulin resistance. PRACTICAL APPLICATIONS: Obesity is a risk factor for developing insulin resistance and dyslipidemia. Therefore, there is an increasing interest in consuming foods rich in bioactive compounds as therapeutic alternatives for managing the development of obesity and its complications. Edible insects, such as crickets, are attractive for treating obesity due to their content of protein, fiber, and polyunsaturated fatty acids. Studies have explored the effect of glycosaminoglycan (GAG)-enriched extracts from the cricket Gryllus bimaculatus against obesity. However, GAG content in crickets is low, and crickets are commonly consumed whole instead of extracts. The cricket Acheta domesticus (AD) is among the most rearing cricket species as it is easy to farm and has a better flavor. However, limited studies have explored the beneficial effects of AD consumption. This study demonstrates that AD prevents obesity and ameliorates dyslipidemia and insulin resistance. Therefore, AD is a valuable entomotherapeutic strategy to reduce the comorbidities associated with diet-induced obesity.

Maternal Exercise and Paternal Exercise Induce Distinct Metabolite Signatures in Offspring Tissues.

That maternal and paternal exercise improve the metabolic health of adult offspring is well established. Tissue and serum metabolites play a fundamental role in the health of an organism, but how parental exercise affects offspring tissue and serum metabolites has not yet been investigated. Here, male and female breeders were fed a high-fat diet and housed with or without running wheels before breeding (males) and before and during gestation (females). Offspring were sedentary and chow fed, with parents as follows: sedentary (Sed), maternal exercise (MatEx), paternal exercise (PatEx), or maternal+paternal exercise (Mat+PatEx). Adult offspring from all parental exercise groups had similar improvement in glucose tolerance and hepatic glucose production. Targeted metabolomics was performed in offspring serum, liver, and triceps muscle. Offspring from MatEx, PatEx, and Mat+PatEx each had a unique tissue metabolite signature, but Mat+PatEx offspring had an additive phenotype relative to MatEx or PatEx alone in a subset of liver and muscle metabolites. Tissue metabolites consistently indicated that the metabolites altered with parental exercise contribute to enhanced fatty acid oxidation. These data identify distinct tissue-specific adaptations and mechanisms for parental exercise-induced improvement in offspring metabolic health. Further mining of this data set could aid the development of novel therapeutic targets to combat metabolic diseases.

Caloric restriction following early-life high fat-diet feeding represses skeletal muscle TNF in male rats.

Chronic metabolic diseases are on the rise worldwide and their etiology is multifactorial. Among them, inflammatory components like Tumor Necrosis Factor (TNF), contribute to whole-body metabolic impairment. Caloric Restriction (CR) combats metabolic diseases, but how it reduces inflammation remains understudied. We aimed to evaluate the impact of chronic CR on muscle inflammation, in particular TNF. In our study, 4-week old male Sprague-Dawley rats were fed a high-fat diet (HF, 45% Kcal of fat from lard) ad libitum for 3 months. After estimation of their energy requirement (1 month), they were then divided into three groups: HF ad libitum (OL), weight maintenance with AIN93M (9.5% Kcal from fat; ML, 100% of energy requirement), and caloric restriction (CR, AIN93M with 75% of energy requirement). This dietary intervention continued for six months. At this point, rats were sacrificed and gastrocnemius muscle was collected. CR induced a profound shift in fat and lean mass, and decreased growth factor IGF-1. Muscle qPCR analysis showed a marked decrease in inflammation and TNF (premRNA, mRNA, and protein) by CR, accompanied by Tnf promoter DNA hypermethylation. CR increased expression of histone deacetylase Sirt6 and decreased methyltransferase Suv39h1, together with decreased Tnf promoter and coding region binding of NF- κB and C/EBP-ß. Following miRNA database mining, qPCR analysis revealed that CR downregulated the proinflammatory miR-19b and increased the anti-inflammatory miR-181a and its known targets. Chronic CR is able to regulate muscle-specific inflammation by targeting the NF-κB pathway as well as transcriptional and post-transcriptional regulation of Tnf gene.

Weight loss with exercise improves muscle architecture and progenitor cell populations compared with weight loss alone in mice with preneoplastic colorectal lesions.

Weight loss and exercise reduce colorectal cancer (CRC) risk in persons with obesity. Whether weight loss and exercise effect myofiber characteristics and muscle stem/progenitor cell populations in mice with preneoplastic colorectal lesions, a model of CRC risk, is unknown. To address this gap, male C57Bl/6J mice were fed a high-fat diet (HFD) to induce obesity or a control (CON) diet prior to azoxymethane injection to induce preneoplastic colorectal lesions. The HFD group was then randomized to weight loss conditions that included (1) switching to the CON diet only (HFD-SED) or switching to the CON diet with treadmill exercise training (HFD-EX). Average myofiber cross-sectional area was not different between groups. There were more smaller-sized fibres in HFD-EX (p < 0.05 vs. CON), and more fibrosis in HFD-SED (p < 0.05 vs. HFD-EX and CON). There was a trend for more committed (Pax7+MyoD+) myoblasts (p = 0.059) and more fibro-adipogenic progenitors in HFD-EX (p < 0.05 vs. CON). Additionally, the canonical pro-inflammatory marker p-NF-κB was markedly reduced in the interstitium of HFD-EX (p < 0.05 vs. CON and HFD-SED). Our findings suggest that in mice with preneoplastic colorectal lesions, HFD followed by weight loss with exercise reduces muscle fibrosis and results in a higher content of muscle stem/progenitor cells. Novelty: Exercise improves muscle architecture in mice with preneoplastic colorectal lesion Exercise increases fibro/adipogenic progenitors and reduces inflammatory signaling in mice with preneoplastic colorectal lesions.

The Regulation of Lipokines by Environmental Factors.

Adipose tissue is a highly metabolically-active tissue that senses and secretes hormonal and lipid mediators that facilitate adaptations to metabolic tissues. In recent years, the role of lipokines, which are lipid species predominantly secreted from adipose tissue that act as hormonal regulators in many metabolic tissues, has been an important area of research for obesity and diabetes. Previous studies have identified that these secreted lipids, including palmitoleate, 12,13-diHOME, and fatty acid-hydroxy-fatty acids (FAHFA) species, are important regulators of metabolism. Moreover, environmental factors that directly affect the secretion of lipokines such as diet, exercise, and exposure to cold temperatures constitute attractive therapeutic strategies, but the mechanisms that regulate lipokine stimulation have not been thoroughly reviewed. In this study, we will discuss the chemical characteristics of lipokines that position them as attractive targets for chronic disease treatment and prevention and the emerging roles of lipokines as regulators of inter-tissue communication. We will define the target tissues of lipokines, and explore the ability of lipokines to prevent or delay the onset and development of chronic diseases. Comprehensive understanding of the lipokine synthesis and lipokine-driven regulation of metabolic outcomes is instrumental for developing novel preventative and therapeutic strategies that harness adipose tissue-derived lipokines.

Epigenetic Regulation of Metabolism and Inflammation by Calorie Restriction.

Chronic caloric restriction (CR) without malnutrition is known to affect different cellular processes such as stem cell function, cell senescence, inflammation, and metabolism. Despite the differences in the implementation of CR, the reduction of calories produces a widespread beneficial effect in noncommunicable chronic diseases, which can be explained by improvements in immuno-metabolic adaptation. Cellular adaptation that occurs in response to dietary patterns can be explained by alterations in epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA. In this review, we define these modifications and systematically summarize the current evidence related to CR and the epigenome. We then explain the significance of genome-wide epigenetic modifications in the context of disease development. Although substantial evidence exists for the widespread effect of CR on longevity, there is no consensus regarding the epigenetic regulations of the underlying cellular mechanisms that lead to improved health. We provide compelling evidence that CR produces long-lasting epigenetic effects that mediate expression of genes related to immuno-metabolic processes. Epigenetic reprogramming of the underlying chronic low-grade inflammation by CR can lead to immuno-metabolic adaptations that enhance quality of life, extend lifespan, and delay chronic disease onset.

Cold and Exercise: Therapeutic Tools to Activate Brown Adipose Tissue and Combat Obesity.

The rise in obesity over the last several decades has reached pandemic proportions. Brown adipose tissue (BAT) is a thermogenic organ that is involved in energy expenditure and represents an attractive target to combat both obesity and type 2 diabetes. Cold exposure and exercise training are two stimuli that have been investigated with respect to BAT activation, metabolism, and the contribution of BAT to metabolic health. These two stimuli are of great interest because they have both disparate and converging effects on BAT activation and metabolism. Cold exposure is an effective mechanism to stimulate BAT activity and increase glucose and lipid uptake through mitochondrial uncoupling, resulting in metabolic benefits including elevated energy expenditure and increased insulin sensitivity. Exercise is a therapeutic tool that has marked benefits on systemic metabolism and affects several tissues, including BAT. Compared to cold exposure, studies focused on BAT metabolism and exercise display conflicting results; the majority of studies in rodents and humans demonstrate a reduction in BAT activity and reduced glucose and lipid uptake and storage. In addition to investigations of energy uptake and utilization, recent studies have focused on the effects of cold exposure and exercise on the structural lipids in BAT and secreted factors released from BAT, termed batokines. Cold exposure and exercise induce opposite responses in terms of structural lipids, but an important overlap exists between the effects of cold and exercise on batokines. In this review, we will discuss the similarities and differences of cold exposure and exercise in relation to their effects on BAT activity and metabolism and its relevance for the prevention of obesity and the development of type 2 diabetes.

Effects of Obesity and Exercise on Bone Marrow Progenitor Cells after Radiation.

INTRODUCTION: The late effects of radiation therapy can have significant consequences for the health and quality of life of long-term cancer survivors. Radiation induces persistent alterations in hematopoietic stem and progenitor cells (HSPC) and the bone marrow environment; however, how relevant host factors such as obesity and exercise differentially regulate HSPC content and the bone marrow environment after radiation exposure remains unknown. The purpose of this investigation was to evaluate how the combination of obesity and exercise training modulates HSPC and their niche after sublethal radiation exposure in mice. METHODS: Mice fed either a control or a high-fat diet to induce obesity remained sedentary or underwent a progressive treadmill exercise program. At 13 wk of age, mice were irradiated (3 Gy) and continued their specific diets and exercise program for four more weeks. RESULTS: Exercise-trained mice had significantly higher quantities of several HSPC subpopulations and bone marrow stromal cell populations, whereas HSPC subpopulations were significantly lower in obese mice after radiation. Reactive oxygen species content was significantly decreased in HSPC with exercise training. Proteomics analysis of bone marrow supernatant revealed clustering of biologically relevant changes in exercise-trained mice. Functional evaluation of bone marrow supernatant revealed a significant increase in leukemia blast viability in obese mice but not in the exercise-trained mice (P < 0.05). CONCLUSION: Together, these data suggest that exercise training partially restores the negative effects of obesity on HSPC and their niche after radiation exposure. As such, exercise training should be considered to mitigate the late effects of radiation therapy on the hematopoietic system for cancer survivors with or without obesity who have undergone radiation therapy.

Tissue-specific changes in Srebf1 and Srebf2 expression and DNA methylation with perinatal phthalate exposure.

Perinatal exposure to endocrine disrupting chemicals negatively impacts health, but the mechanism by which such toxicants damage long-term reproductive and metabolic function is unknown. Lipid metabolism plays a pivotal role in steroid hormone synthesis as well as energy utilization and storage; thus, aberrant lipid regulation may contribute to phthalate-driven health impairments. In order to test this hypothesis, we specifically examined epigenetic disruptions in lipid metabolism pathways after perinatal phthalate exposure. During gestation and lactation, pregnant Long-Evans rat dams were fed environmentally relevant doses of phthalate mixture: 0 (CON), 200 (LO), or 1000 (HI) µg/kg body weight/day. On PND90, male offspring in the LO and HI groups had higher body weights than CON rats. Gene expression of lipid metabolism pathways was altered in testis and adipose tissue of males exposed to the HI phthalate dosage. Specifically, Srebf1 was downregulated in testis and Srebf2 was upregulated in adipose tissue. In testis of HI rats, DNA methylation was increased at two loci and reduced at one other site surrounding Srebf1 transcription start site. In adipose tissue of HI rats, we observed increased DNA methylation at one region within the first intron of Srebf2. Computational analysis revealed several potential transcriptional regulator binding sites, suggesting functional relevance of the identified differentially methylated CpGs. Overall, we show that perinatal phthalate exposure affects lipid metabolism gene expression in a tissue-specific manner possibly through altering DNA methylation of Srebf1 and Srebf2.