Search

Abstract Background Cattle shedding at least 104 CFU Escherichia coli O157:H7/g feces are described as super-shedders and have been shown to increase transmission of E. coli O157:H7 to other cattle in feedlots. This study investigated relationships among fecal isolates from super-shedders (n = 162), perineal hide swab isolates (PS) from super-shedders (n = 137) and fecal isolates from low-shedder (< 104 CFU/g feces) pen-mates (n = 496) using pulsed-field gel electrophoresis (PFGE). A subsample of these fecal isolates (n = 474) was tested for antimicrobial resistance. Isolates of E. coli O157:H7 were obtained from cattle in pens (avg. 181 head) at 2 commercial feedlots in southern Alberta with each steer sampled at entry to the feedlot and prior to slaughter. Results Only 1 steer maintained super-shedder status at both samplings, although approximately 30% of super-shedders in sampling 1 had low-shedder status at sampling 2. A total of 85 restriction endonuclease digestion clusters (REPC; 90% or greater similarity) and 86 unique isolates (< 90% similarity) were detected, with the predominant REPC (30% of isolates) being isolated from cattle in all feedlot pens, although it was not associated with shedding status (super- or low-shedder; P = 0.94). Only 2/21 super-shedders had fecal isolates in the same REPC at both samplings. Fecal and PS isolates from individual super-shedders generally belonged to different REPCs, although fecal isolates of E. coli O157:H7 from super- and low-shedders showed greater similarity (P P = 0.69), although all super-shedder isolates with antimicrobial resistance (n = 3) were resistant to multiple antimicrobials. Conclusions Super-shedders did not have increased antimicrobial resistance compared to low-shedder pen mates. Our data demonstrated that PFGE profiles of individual super-shedders varied over time and that only 1/162 steers remained a super-shedder at 2 samplings. In these two commercial feedlots, PFGE subtypes of E. coli O157:H7 from fecal isolates of super- and low-shedders were frequently different as were subtypes of fecal and perineal hide isolates from super-shedders.

Abstract Background One of the most effective targets for control of zoonotic foodborne pathogens in the farm to fork continuum is their elimination in food animals destined for market. Phage therapy for Escherichia coli O157:H7 in ruminants, the main animal reservoir of this pathogen, is a popular research topic. Since phages active against this pathogen may be endemic in host animals and their environment, they may emerge during trials of phage therapy or other interventions, rendering interpretation of trials problematic. Methods During separate phage therapy trials, sheep and cattle inoculated with 109 to 1010 CFU of E. coli O157:H7 soon began shedding phages dissimilar in plaque morphology to the administered therapeutic phages. None of the former was previously identified in the animals or in their environment. The dissimilar “rogue” phage was isolated and characterized by host range, ultrastructure, and genomic and proteomic analyses. Results The “rogue” phage (Phage vB_EcoS_Rogue1) is distinctly different from the administered therapeutic Myoviridae phages, being a member of the Siphoviridae (head: 53 nm; striated tail: 152 x 8 nm). It has a 45.8 kb genome which is most closely related to coliphage JK06, a member of the “T1-like viruses” isolated in Israel. Detailed bioinformatic analysis reveals that the tail of these phages is related to the tail genes of coliphage lambda. The presence of “rogue” phages resulting from natural enrichments can pose problems in the interpretation of phage therapeutic studies. Similarly, evaluation of any interventions for foodborne or other bacterial pathogens in animals may be compromised unless tests for such phages are included to identify their presence and potential impact.

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with higher rates of recurrence and distant metastasis, as well as decreased 5-year survival rates. Racial disparities are evident in the incidence and mortality rates of triple negative breast cancer particularly increased in young African American women. Concurrently, young African American women have multiple risk factors for TNBC including higher rates of premenopausal abdominal obesity (higher waist-hip ratio) and lower rates of breastfeeding with higher parity, implicating these factors as potentially contributors to poor outcomes. By understanding the mechanisms of how premenopausal obesity and lack of breastfeeding may be associated with increased risk of triple negative breast cancer, we can determine the best strategies for intervention and awareness to improve outcomes in TNBC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ormiston, Kulkarni, Sarathy, Alsammerai, Shankar, Majumder, Stanford, Ganju and Ramaswamy.)

Metabolic diseases, notably obesity and type 2 diabetes (T2D), have reached alarming proportions and constitute a significant global health challenge, emphasizing the urgent need for effective preventive and therapeutic strategies. In contrast, exercise training emerges as a potent intervention, exerting numerous positive effects on metabolic health through adaptations to the metabolic tissues. Here, we reviewed the major features of our current understanding with respect to the intricate interplay between metabolic diseases and key metabolic tissues, including adipose tissue, skeletal muscle, and liver, describing some of the main underlying mechanisms driving pathogenesis, as well as the role of exercise to combat and treat obesity and metabolic disease.

Exercise training and cold exposure both improve systemic metabolism, but the mechanisms are not well established. Here, we tested the hypothesis that inguinal white adipose tissue (iWAT) adaptations are critical for these beneficial effects and determined the impact of exercise-trained and cold-exposed iWAT on systemic glucose metabolism and the iWAT proteome and secretome. Transplanting trained iWAT into sedentary mice improves glucose tolerance, while cold-exposed iWAT transplantation shows no such benefit. Compared to training, cold leads to more pronounced alterations in the iWAT proteome and secretome, downregulating >2,000 proteins but also boosting the thermogenic capacity of iWAT. In contrast, only training increases extracellular space and vesicle transport proteins, and only training upregulates proteins that correlate with favorable fasting glucose, suggesting fundamental changes in trained iWAT that mediate tissue-to-tissue communication. This study defines the unique exercise training- and cold exposure-induced iWAT proteomes, revealing distinct mechanisms for the beneficial effects of these interventions on metabolic health., Competing Interests: Declaration of interests R.J.W.M. and L.J.G. have received research support from Novo Nordisk, which is unrelated to the present study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neonatal sepsis remains one of the leading causes of mortality in newborns. Several brainstem-regulated physiological processes undergo disruption during neonatal sepsis. Mechanistic knowledge gaps exist at the interplay between metabolism and immune activation to brainstem neural circuits and pertinent physiological functions in neonates. To delineate this association, we induced systemic inflammation either by TLR4 (LPS) or TLR1/2 (PAM3CSK4) ligand administration in postnatal day 5 mice (PD5). Our findings show that LPS and PAM3CSK4 evoke substantial changes in respiration and metabolism. Physiological trade-offs led to hypometabolic-hypothermic responses due to LPS, but not PAM3CSK4, whereas to both TLR ligands blunted respiratory chemoreflexes. Neuroinflammatory pathways modulation in brainstem showed more robust effects in LPS than PAM3CSK4. Brainstem neurons, microglia, and astrocyte gene expression analyses showed unique responses to TLR ligands. PAM3CSK4 did not significantly modulate gene expression changes in GLAST-1 positive brainstem astrocytes. PD5 pups receiving PAM3CSK4 failed to maintain a prolonged metabolic state repression, which correlated to enhanced gasping latency and impaired autoresuscitation during anoxic chemoreflex challenges. In contrast, LPS administered pups showed no significant changes in anoxic chemoreflex. Electrophysiological studies from brainstem slices prepared from pups exposed to either TLR4 or PAM3CSK4 showed compromised transmission between preBötzinger complex and Hypoglossal as an exclusive response to the TLR1/2 ligand. Spatial gene expression analysis demonstrated a region-specific modulation of PAM3CSK4 within the raphe nucleus relative to other anatomical sites evaluated. Our findings suggest that metabolic changes due to inflammation might be a crucial tolerance mechanism for neonatal sepsis preserving neural control of breathing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Brown adipose tissue (BAT) is correlated to cardiovascular health in rodents and humans, but the physiological role of BAT in the initial cardiac remodeling at the onset of stress is unknown. Activation of BAT via 48 h cold (16°C) in mice following transverse aortic constriction (TAC) reduced cardiac gene expression for LCFA uptake and oxidation in male mice and accelerated the onset of cardiac metabolic remodeling, with an early isoform shift of carnitine palmitoyltransferase 1 (CPT1) toward increased CPT1a, reduced entry of long chain fatty acid (LCFA) into oxidative metabolism (0.59 ± 0.02 vs. 0.72 ± 0.02 in RT TAC hearts, p < .05) and increased carbohydrate oxidation with altered glucose transporter content. BAT activation with TAC reduced early hypertrophic expression of β-MHC by 61% versus RT-TAC and reduced pro-fibrotic TGF-β1 and COL3α1 expression. While cardiac natriuretic peptide expression was yet to increase at only 3 days TAC, Nppa and Nppb expression were elevated in Cold TAC versus RT TAC hearts 2.7- and 2.4-fold, respectively. Eliminating BAT thermogenic activation with UCP1 KO mice eliminated differences between Cold TAC and RT TAC hearts, confirming effects of BAT activation rather than autonomous cardiac responses to cold. Female responses to BAT activation were blunted, with limited UCP1 changes with cold, partly due to already activated BAT in females at RT compared to thermoneutrality. These data reveal a previously unknown physiological mechanism of UCP1-dependent BAT activation in attenuating early cardiac hypertrophic and profibrotic signaling and accelerating remodeled metabolic activity in the heart at the onset of cardiac stress., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

We assessed aging hallmarks in skin, muscle, and adipose in the genetically diverse HET3 mouse, and generated a broad dataset comparing these to individual animal diagnostic SNPs from the 4 founding inbred strains of the HET3 line. For middle- and old-aged HET3 mice, we provided running wheel exercise to ensure our observations were not purely representative of sedentary animals, but age-related phenotypes were not improved with running wheel activity. Adipose tissue fibrosis, peripheral neuropathy, and loss of neuromuscular junction integrity were consistent phenotypes in older-aged HET3 mice regardless of physical activity, but aspects of these phenotypes were moderated by the SNP% contributions of the founding strains for the HET3 line. Taken together, the genetic contribution of founder strain SNPs moderated age-related phenotypes in skin and muscle innervation and were dependent on biological sex and chronological age. However, there was not a single founder strain (BALB/cJ, C57BL/6J, C3H/HeJ, DBA/2J) that appeared to drive more protection or disease-risk across aging in this mouse line, but genetic diversity in general was more protective., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The intrauterine environment during pregnancy is a critical factor in the development of obesity, diabetes, and cardiovascular disease in offspring. Maternal exercise prevents the detrimental effects of a maternal high fat diet on the metabolic health in adult offspring, but the effects of maternal exercise on offspring cardiovascular health have not been thoroughly investigated., Methods: To determine the effects of maternal exercise on offspring cardiovascular health, female mice were fed a chow (C; 21% kcal from fat) or high-fat (H; 60% kcal from fat) diet and further subdivided into sedentary (CS, HS) or wheel exercised (CW, HW) prior to pregnancy and throughout gestation. Offspring were maintained in a sedentary state and chow-fed throughout 52 weeks of age and subjected to serial echocardiography and cardiomyocyte isolation for functional and mechanistic studies., Results: High-fat fed sedentary dams (HS) produced female offspring with reduced ejection fraction (EF) compared to offspring from chow-fed dams (CS), but EF was preserved in offspring from high-fat fed exercised dams (HW) throughout 52 weeks of age. Cardiomyocytes from HW female offspring had increased kinetics, calcium cycling, and respiration compared to CS and HS offspring. HS offspring had increased oxidation of the RyR2 in cardiomyocytes coupled with increased baseline sarcomere length, resulting in RyR2 overactivity, which was negated in female HW offspring., Conclusions: These data suggest a role for maternal exercise to protect against the detrimental effects of a maternal high-fat diet on female offspring cardiac health. Maternal exercise improved female offspring cardiomyocyte contraction, calcium cycling, respiration, RyR2 oxidation, and RyR2 activity. These data present an important, translatable role for maternal exercise to preserve cardiac health of female offspring and provide insight on mechanisms to prevent the transmission of cardiovascular diseases to subsequent generations., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

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 β-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 Ca 2+ 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., Competing Interests: P.M.C. is a consultant for Astellas/Mitobridge, Incorporate. K.I.S. is a consultant for Lygenesis., (© 2024 The Author(s).)

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., Competing Interests: M.D.W., R.S., H.S., and N.N.M. are employed by AgeX Therapeutics., (© 2024 The Author(s).)

Exercise has systemic health benefits through effects on multiple tissues, with intertissue communication. Recent studies indicate that exercise may improve breastmilk composition and thereby reduce the intergenerational transmission of obesity. Even if breastmilk is considered optimal infant nutrition, there is evidence for variations in its composition between mothers who are normal weight, those with obesity, and those who are physically active. Nutrition early in life is important for later-life susceptibility to obesity and other metabolic diseases, and maternal exercise may provide protection against the development of metabolic disease. Here we summarize recent research on the influence of maternal obesity on breastmilk composition and discuss the potential role of exercise-induced adaptations to breastmilk as a kick-start to prevent childhood obesity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Autologous adipose tissue is commonly used for tissue engraftment for the purposes of soft tissue reconstruction due to its relative abundance in the human body and ease of acquisition using liposuction methods. This has led to the adoption of autologous adipose engraftment procedures that allow for the injection of adipose tissues to be used as a "filler" for correcting cosmetic defects and deformities in soft tissues. However, the clinical use of such methods has several limitations, including high resorption rates and poor cell survivability, which lead to low graft volume retention and inconsistent outcomes. Here, we describe a novel application of milled electrospun poly(lactic-co-glycolic acid) (PLGA) fibers, which can be co-injected with adipose tissue to improve engraftment outcomes. These PLGA fibers had no significant negative impact on the viability of adipocytes in vitro and did not elicit long-term proinflammatory responses in vivo. Furthermore, co-delivery of human adipose tissue with pulverized electrospun PLGA fibers led to significant improvements in reperfusion, vascularity, and retention of graft volume compared to injections of adipose tissue alone. Taken together, the use of milled electrospun fibers to enhance autologous adipose engraftment techniques represents a novel approach for improving upon the shortcomings of such methods., (© 2023 The Authors. Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)

Although aging is associated with progressive adiposity and a decline in liver function, the underlying molecular mechanisms and metabolic interplay are incompletely understood. Here, we demonstrate that aging induces hepatic protein kinase Cbeta (PKCβ) expression, while hepatocyte PKCβ deficiency (PKCβ Hep-/- ) in mice significantly attenuates obesity in aged mice fed a high-fat diet. Compared with control PKCβ fl/fl mice, PKCβ Hep-/- mice showed elevated energy expenditure with augmentation of oxygen consumption and carbon dioxide production which was dependent on β3-adrenergic receptor signaling, thereby favoring negative energy balance. This effect was accompanied by induction of thermogenic genes in brown adipose tissue (BAT) and increased BAT respiratory capacity, as well as a shift to oxidative muscle fiber type with an improved mitochondrial function, thereby enhancing oxidative capacity of thermogenic tissues. Furthermore, in PKCβ Hep-/- mice, we determined that PKCβ overexpression in the liver mitigated elevated expression of thermogenic genes in BAT. In conclusion, our study thus establishes hepatocyte PKCβ induction as a critical component of pathophysiological energy metabolism by promoting progressive hepatic and extrahepatic metabolic derangements in energy homeostasis, contributing to late-onset obesity. These findings have potential implications for augmenting thermogenesis as a means of combating aging-induced obesity., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Exercise induces various beneficial whole-body adaptations and can delay the onset of obesity, type 2 diabetes, and cardiovascular disease. While many of the beneficial effects of exercise on skeletal muscle and the cardiovascular system have been well established, recent studies have highlighted the role of exercise-induced improvements to adipose tissue that affect metabolic and whole-body health. Studies investigating exercise-induced adaptations of white adipose tissue (WAT) and brown adipose tissue (BAT) demonstrate modifications to glucose uptake, mitochondrial activity, and endocrine profile, and a beiging of WAT in rodents. This review discusses recent studies of the exercise-induced adaptations to WAT and BAT and their implications., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Exercise physiology has gained increasing interest due to its wide effects to promote health. Recent years have seen a growth in this research field also due to the finding of several circulating factors that mediate the effects of exercise. These factors, termed exerkines, are metabolites, growth factors, and cytokines secreted by main metabolic organs during exercise to regulate exercise systemic and tissue-specific effects. The metabolic effects of exerkines have been broadly explored and entail a promising target to modulate beneficial effects of exercise in health and disease. However, exerkines also have broad effects to modulate redox signaling and homeostasis in several cellular processes to improve stress response. Since redox biology is central to exercise physiology, this review summarizes current evidence for the cross-talk between redox biology and exerkines actions. The role of exerkines in redox biology entails a response to oxidative stress-induced pathological cues to improve health outcomes and to modulate exercise adaptations that integrate redox signaling., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The use of electronic nicotine delivery systems, specifically electronic cigarettes (e-cig), has risen dramatically within the last few years; the demographic purchasing these devices is now predominantly adolescents that are not trying to quit the use of traditional combustible cigarettes, but rather are new users. The composition and appearance of these devices has changed since their first entry into the market in the late 2000s, but they remain composed of a battery and aerosol delivery system that is used to deliver breakdown products of propylene glycol/vegetable glycerin, flavorings, and potentially nicotine or other additives. Manufacturers have also adjusted the type of nicotine that is used within the liquid to make the inhalation more palatable for younger users, further affecting the number of youth who use these devices. Although the full spectrum of cardiovascular and cardiometabolic consequences of e-cig use is not fully appreciated, data is beginning to show that e-cigs can cause both short- and long-term issues on cardiac function, vascular integrity and cardiometabolic issues. This review will provide an overview of the cardiovascular, cardiometabolic, and vascular implications of the use of e-cigs, and the potential short- and long-term health effects. A robust understanding of these effects is important in order to inform policy makers on the dangers of e-cigs use.

Exercise leads to numerous beneficial whole-body effects and can protect against the development of obesity, cardiometabolic, and neurodegenerative diseases. Recent studies have highlighted the importance of inter-organ crosstalk with a focus on secretory factors that mediate communication among organs, including adipose tissue and the heart. Studies investigating the effects of exercise on brown adipose tissue (BAT) and white adipose tissue (WAT) demonstrated that adipokines are released in response to exercise and act on the heart to decrease inflammation, alter gene expression, increase angiogenesis, and improve cardiac function. This review discusses the exercise-induced adaptations to BAT and WAT and how these adaptations affect heart health and function, while highlighting the importance of tissue crosstalk., Competing Interests: Conflict of Interest The authors have no potential conflicts of interest to disclose.

Limb-girdle muscular dystrophy type R25 (LGMDR25) is caused by recessive mutations in BVES encoding a cAMP-binding protein, characterized by progressive muscular dystrophy with deteriorating muscle function and impaired cardiac conduction in patients. There is currently no therapeutic treatment for LGMDR25 patients. Here we report the efficacy and safety of recombinant adeno-associated virus 9 (AAV9)-mediated systemic delivery of human BVES driven by a muscle-specific promoter MHCK7 (AAV9.BVES) in BVES-knockout (BVES-KO) mice. AAV9.BVES efficiently transduced the cardiac and skeletal muscle tissues when intraperitoneally injected into neonatal BVES-KO mice. AAV9.BVES dramatically improved body weight gain, muscle mass, muscle strength, and exercise performance in BVES-KO mice regardless of sex. AAV9.BVES also significantly ameliorated the histopathological features of muscular dystrophy. The heart rate reduction was also normalized in BVES-KO mice under exercise-induced stress following systemic AAV9.BVES delivery. Moreover, intravenous AAV9.BVES administration into adult BVES-KO mice after the disease onset also resulted in substantial improvement in body weight, muscle mass, muscle contractility, and stress-induced heart rhythm abnormality. No obvious toxicity was detected. Taken together, these results provide the proof-of-concept evidence to support the AAV9.BVES gene therapy for LGMDR25., Competing Interests: Declaration of interests R.H. and H.L. have submitted a patent application based on the results reported in this manuscript., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Aerobic exercise is an important component of rehabilitation after cardiovascular injuries including myocardial infarction (MI). In human studies, the beneficial effects of exercise after an MI are blunted in patients who are obese or glucose intolerant. Here, we investigated the effects of exercise on MI-induced cardiac dysfunction and remodeling in mice chronically fed a high-fat diet (HFD)., Main Methods: C57Bl/6 male mice were fed either a standard (Chow; 21% kcal/fat) or HFD (60% kcal/fat) for 36 weeks. After 24 weeks of diet, the HFD mice were randomly subjected to an MI (MI) or a sham surgery (Sham). Following the MI or sham surgery, a subset of mice were subjected to treadmill exercise., Key Findings: HFD resulted in obesity and glucose intolerance, and this was not altered by exercise or MI. MI resulted in decreased ejection fraction, increased left ventricle mass, increased end systolic and diastolic diameters, increased cardiac fibrosis, and increased expression of genes involved in cardiac hypertrophy and heart failure in the MI-Sed and MI-Exe mice. Exercise prevented HFD-induced cardiac fibrosis in Sham mice (Sham-Exe) but not in MI-Exe mice. Exercise did, however, reduce post-MI mortality., Significance: These data indicate that exercise significantly increased survival after MI in a model of diet-induced obesity independent of effects on cardiac function. These data have important translational ramifications because they demonstrate that environmental interventions, including diet, need to be carefully evaluated and taken into consideration to support the effects of exercise in the cardiac rehabilitation of patients who are obese., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2022 by the American Diabetes Association.)

Decreased adipose tissue regulatory T cells contribute to insulin resistance in obese mice, however, little is known about the mechanisms regulating adipose tissue regulatory T cells numbers in humans. Here we obtain adipose tissue from obese and lean volunteers. Regulatory T cell abundance is lower in obese vs. lean visceral and subcutaneous adipose tissue and associates with reduced insulin sensitivity and altered adipocyte metabolic gene expression. Regulatory T cells numbers decline following high-fat diet induction in lean volunteers. We see alteration in major histocompatibility complex II pathway in adipocytes from obese patients and after high fat ingestion, which increases T helper 1 cell numbers and decreases regulatory T cell differentiation. We also observe increased expression of inhibitory co-receptors including programmed cell death protein 1 and OX40 in visceral adipose tissue regulatory T cells from patients with obesity. In human obesity, these global effects of interferon gamma to reduce regulatory T cells and diminish their function appear to instigate adipose inflammation and suppress adipocyte metabolism, leading to insulin resistance., (© 2022. The Author(s).)

Obesity is increasing at epidemic rates across the US and worldwide, as are its co-morbidities, including type-2 diabetes and cardiovascular disease. Thus, targeted interventions to reduce the prevalence of obesity are of the utmost importance. The sigma-1 receptor (S1R) and sigma-2 receptor (S2R; encoded by Tmem97 ) belong to the same class of drug-binding sites, yet they are genetically distinct. There are multiple ongoing clinical trials focused on sigma receptors, targeting diseases ranging from Alzheimer's disease through chronic pain to COVID-19. However, little is known regarding their gene-specific role in obesity. In this study, we measured body composition, used a comprehensive laboratory-animal monitoring system, and determined the glucose and insulin tolerance in mice fed a high-fat diet. Compared to Sigmar1+/+ mice of the same sex, the male and female Sigmar1-/- mice had lower fat mass (17% and 12% lower, respectively), and elevated lean mass (16% and 10% higher, respectively), but S1R ablation had no effect on their metabolism. The male Tmem97-/- mice exhibited 7% lower fat mass, 8% higher lean mass, increased volumes of O 2 and CO 2 , a decreased respiratory exchange ratio indicating elevated fatty-acid oxidation, and improved insulin tolerance, compared to the male Tmem97+/+ mice. There were no changes in any of these parameters in the female Tmem97-/- mice. Together, these data indicate that the S1R ablation in male and female mice or the S2R ablation in male mice protects against diet-induced adiposity, and that S2R ablation, but not S1R deletion, improves insulin tolerance and enhances fatty-acid oxidation in male mice. Further mechanistic investigations may lead to translational strategies to target differential S1R/S2R regulations and sexual dimorphism for precision treatments of obesity.

Brown adipose tissue (BAT) is a metabolically active tissue that improves glucose metabolism and protects against the development of type 2 diabetes and obesity. However, the role of BAT to improve cardiovascular health has only recently been investigated. In this review, we discuss multiple mechanisms through which both the thermogenic and endocrine functions of BAT mediate cardiac health. β -adrenergic stimulation activates the thermogenic function of BAT, resulting in reduced circulating lipids and glucose, and enhanced clearance of hepatic cholesterol-enriched remnants leading to reduced atherosclerotic region size. Additionally, the thermogenic role of BAT has been implicated in activation of the protein kinase B-extracellular-signal-regulated kinase (ERK) 1/2 pathway after myocardial infarction (MI), contributing to reduced injury size. The endocrine function of BAT has also been implicated to improve both systemic metabolic health and cardiac health. Specifically, the batokines fibroblast growth factor 21 (FGF21) and 12,13-diHOME improve cardiovascular health via reduced hypertension, hypertrophy and MI injury size (FGF21) or by directly improving cardiac function via calcium cycling (12,13-diHOME). Finally, we discuss relevant pharmacological treatment methods currently aiming to activate BAT, typically through sympathetic activation. SIGNIFICANCE STATEMENT: This mini-review discusses the role of BAT to improve cardiac health via thermogenic and endocrine effects in both rodents and humans and highlights the need for therapeutic methods which activate or mimic BAT activity., (Copyright © 2022 by The Author(s).)

The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions., (© 2022. Springer Nature Limited.)

The prevalence of metabolic diseases is rapidly increasing and a principal contributor to this is diet, including increased consumption of energy-rich foods and foods with added phosphates. Exercise is an effective therapeutic approach to combat metabolic disease. While exercise is effective to combat the detrimental effects of a high-fat diet on metabolic health, the effects of exercise on a high-phosphate diet have not been thoroughly investigated. Here, we investigated the effects of a high-fat or high-phosphate diet in the presence or absence of voluntary exercise on metabolic function in male mice. To do this, mice were fed a low-fat, normal-phosphate diet (LFPD), a high-phosphate diet (HPD) or a high-fat diet (HFD) for 6 weeks and then subdivided into either sedentary or exercised (housed with running wheels) for an additional 8 weeks. An HFD severely impaired metabolic function in mice, increasing total fat mass and worsening whole-body glucose tolerance, while HPD did not induce any notable effects on glucose metabolism. Exercise reverted most of the detrimental metabolic adaptations induced by HFD, decreasing total fat mass and restoring whole-body glucose tolerance and insulin sensitivity. Interestingly, voluntary exercise had a similar effect on LFPD and HPD mice. These data suggest that a high-phosphate diet does not significantly impair glucose metabolism in sedentary or voluntary exercised conditions.

Purpose of Review: This review highlights aspects of brown adipose tissue (BAT) communication with other organ systems and how BAT-to-tissue cross-talk could help elucidate future obesity treatments., Recent Findings: Until recently, research on BAT has focused mainly on its thermogenic activity. New research has identified an endocrine/paracrine function of BAT and determined that many BAT-derived molecules, termed "batokines," affect the physiology of a variety of organ systems and cell types. Batokines encompass a variety of signaling molecules including peptides, metabolites, lipids, or microRNAs. Recent studies have noted significant effects of batokines on physiology as it relates whole-body metabolism and cardiac function. This review will discuss batokines and other BAT processes that affect the liver, cardiovascular system, skeletal muscle, immune cells, and brown and white adipose tissue. Brown adipose tissue has a crucial secretory function that plays a key role in systemic physiology., (© 2022. The Author(s).)

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., (© 2021. The Author(s).)

Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves inter-organ communication. Understanding the mechanisms controlling systemic cross-talk for the maintenance of metabolic health is critical to counteract diet-induced obesity. Here, we show that cardiac-derived transforming growth factor beta 1 (TGF-β1) protects against weight gain and glucose intolerance in mice subjected to high-fat diet. Secretion of TGF-β1 by cardiomyocytes correlates with the bioavailability of this factor in circulation. TGF-β1 prevents adipose tissue inflammation independent of body mass and glucose metabolism phenotypes, indicating protection from adipocyte dysfunction-driven immune cell recruitment. TGF-β1 alters the gene expression programs in white adipocytes, favoring their fatty acid oxidation and consequently increasing their mitochondrial oxygen consumption rates. Ultimately, subcutaneous and visceral white adipose tissue from cadiac-specific TGF-β1 transgenic mice fail to undergo cellular hypertrophy, leading to reduced overall adiposity during high-fat feeding. Thus, TGF-β1 is a critical mediator of heart-fat communication for the regulation of systemic metabolism., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Slit2 exerts antitumor effects in various cancers; however, the underlying mechanism, especially its role in regulating the immune, especially in the bone marrow niche, system is still unknown. Elucidating the behavior of macrophages in tumor progression can potentially improve immunotherapy. Using a spontaneous mammary tumor virus promoter-polyoma middle T antigen (PyMT) breast cancer mouse model, we observed that Slit2 increased the abundance of antitumor M1 macrophage in the bone marrow upon differentiation in vitro . Moreover, myeloablated PyMT mice injected with Slit2-treated bone marrow allografts showed a marked reduction in tumor growth, with enhanced recruitment of M1 macrophage in their tumor stroma. Mechanistic studies revealed that Slit2 significantly enhanced glycolysis and reduced fatty acid oxidation in bone marrow-derived macrophages (BMDMs). Slit2 treatment also altered mitochondrial respiration metabolites in macrophages isolated from healthy human blood that were treated with plasma from breast cancer patients. Overall, this study, for the first time, shows that Slit2 increases BMDM polarization toward antitumor phenotype by modulating immune-metabolism. Furthermore, this study provides evidence that soluble Slit2 could be developed as novel therapeutic strategy to enhance antitumor immune response., Competing Interests: NKJ serves as a consultant for Capture Collective Inc. RKG serves as consultant for Guidepoint consultation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kaul, Benej, Mishra, Ahirwar, Yadav, Stanford, Jacob, Denko and Ganju.)

Influenza A virus (IAV) infection alters lung epithelial cell metabolism in vitro by promoting a glycolytic shift. We hypothesized that this shift benefits the virus rather than the host and that inhibition of glycolysis would improve infection outcomes. A/WSN/33 IAV-inoculated C57BL/6 mice were treated daily from 1 day post-inoculation (d.p.i.) with 2-deoxy-d-glucose (2-DG) to inhibit glycolysis and with the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) to promote flux through the TCA cycle. To block OXPHOS, mice were treated every other day from 1 d.p.i. with the Complex I inhibitor rotenone (ROT). 2-DG significantly decreased nocturnal activity, reduced respiratory exchange ratios, worsened hypoxemia, exacerbated lung dysfunction, and increased humoral inflammation at 6 d.p.i. DCA and ROT treatment normalized oxygenation and airway resistance and attenuated IAV-induced pulmonary edema, histopathology, and nitrotyrosine formation. None of the treatments altered viral replication. These data suggest that a shift to glycolysis is host-protective in influenza., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 (I Na,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 I Na,L in obesity-induced AF using wild-type (WT) and whole-body knock-in mice that ablates phosphorylation of the Na v 1.5 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 Na v 1.5 in mediating susceptibility to arrhythmias and whole-body metabolism under conditions of diet-induced obesity.

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.

Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO 2 and/or O 2 respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal-ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non-cell autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non-cell autonomous maldevelopment of key brainstem respiratory neurons., (© 2020 International Society of Neuropathology.)

The sigma-1 receptor (Sig1R) is a unique ligand-operated endoplasmic reticulum (ER) protein without any mammalian homolog. It has long been a pharmacological target for intervention of psychiatric disorders, and recently garnered refreshed interest for its neuroprotective potential. Though reported to modulate various intracellular events, its influence on cell identity is little known. We explored a role for Sig1R in adipocyte differentiation. We induced adipogenic differentiation of mouse embryonic fibroblasts (MEFs) with a differentiation medium. MEFs were isolated from Sigmar1 -/- and Sigmar1 +/+ mice. The induced adipocyte-like phenotype was detected through Western blots of master transcription factors (PPARγ, CEBPA, SREBP1, SREBP2), lipogenic proteins (FABP4, ACC1, ACAT2), and Oil-Red-O staining of lipids. We found that the induced upregulation of these proteins and lipid accumulation were severely mitigated in Sigmar1 -/- (vs Sigmar1 +/+ ) MEFs. Sig1R activation with a selective agonist (PRE084) increased Sig1R protein and further enhanced the induced adipocyte-like phenotype in Sigmar1 +/+ MEFs. We also determined mouse body weight gain induced by high-fat diet for 6 months, which was impeded in Sigmar1 -/- (vs Sigmar1 +/+ ) male mice. In summary, genetic ablation of Sig1R impairs, and agonist activation of Sig1R enhances adipocyte-like phenotype of induced MEFs. In vivo, Sig1R ablation impedes the body weight gain of male mice on high-fat diet. This study warrants further investigation of a previously unrecognized role for Sig1R in adipocyte differentiation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Type 2 diabetes (T2D) substantially elevates the risk for heart failure, a major cause of death. In advanced T2D, energy metabolism in the heart is disrupted; glucose metabolism is decreased, fatty acid (FA) metabolism is enhanced to maintain ATP production, and cardiac function is impaired. This condition is termed diabetic cardiomyopathy (DCM). The exact cause of DCM is still unknown although altered metabolism is an important component. While type 2 diabetes is characterized by insulin resistance, the traditional antidiabetic agents that improve insulin stimulation or sensitivity only partially improve DCM-induced cardiac dysfunction. Recently, sodium-glucose transporter-2 (SGLT2) inhibitors have been identified as potential pharmacological agents to treat DCM. This review highlights the molecular mechanisms underlying cardiac energy metabolism in DCM, and the potential effects of SGLT2 inhibitors., (Copyright © 2020. Published by Elsevier Ltd.)

Poor maternal environments, such as under- or overnutrition, can increase the risk for the development of obesity, type 2 diabetes and cardiovascular disease in offspring 1-9 . Recent studies in animal models have shown that maternal exercise before and during pregnancy abolishes the age-related development of impaired glucose metabolism 10-15 , decreased cardiovascular function 16 and increased adiposity 11,15 ; however, the underlying mechanisms for maternal exercise to improve offspring's health have not been identified. In the present study, we identify an exercise-induced increase in the oligosaccharide 3'-sialyllactose (3'-SL) in milk in humans and mice, and show that the beneficial effects of maternal exercise on mouse offspring's metabolic health and cardiac function are mediated by 3'-SL. In global 3'-SL knockout mice (3'-SL -/- ), maternal exercise training failed to improve offspring metabolic health or cardiac function in mice. There was no beneficial effect of maternal exercise on wild-type offspring who consumed milk from exercise-trained 3'-SL -/- dams, whereas supplementing 3'-SL during lactation to wild-type mice improved metabolic health and cardiac function in offspring during adulthood. Importantly, supplementation of 3'-SL negated the detrimental effects of a high-fat diet on body composition and metabolism. The present study reveals a critical role for the oligosaccharide 3'-SL in milk to mediate the effects of maternal exercise on offspring's health. 3'-SL supplementation is a potential therapeutic approach to combat the development of obesity, type 2 diabetes and cardiovascular disease.

Differences in glucose uptake in peripheral and neural tissues account for the reduced efficacy of insulin in nervous tissues. Herein, we report the design of short peptides, referred as amino acid compounds (AAC) with and without a modified side chain moiety. At nanomolar concentrations, a candidate therapeutic molecule, AAC2, containing a 7-(diethylamino) coumarin-3-carboxamide side-chain improved glucose control in human peripheral adipocytes and the endothelial brain barrier cells by activation of insulin-insensitive glucose transporter 1 (GLUT1). AAC2 interacted specifically with the leptin receptor (LepR) and activated atypical protein kinase C zeta (PKCς) to increase glucose uptake. The effects induced by AAC2 were absent in leptin receptor-deficient predipocytes and in Lepr db mice. In contrast, AAC2 established glycemic control altering food intake in leptin-deficient Lep ob mice. Therefore, AAC2 activated the LepR and acted in a cytokine-like manner distinct from leptin. In a monogenic Ins2 Akita mouse model for the phenotypes associated with type 1 diabetes, AAC2 rescued systemic glucose uptake in these mice without an increase in insulin levels and adiposity, as seen in insulin-treated Ins2 Akita mice. In contrast to insulin, AAC2 treatment increased brain mass and reduced anxiety-related behavior in Ins2 Akita mice. Our data suggests that the unique mechanism of action for AAC2, activating LepR/PKCς/GLUT1 axis, offers an effective strategy to broaden glycemic control for the prevention of diabetic complications of the nervous system and, possibly, other insulin insensitive or resistant tissues., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Exercise training results in beneficial adaptations to numerous tissues and offers protection against metabolic disorders including obesity and type 2 diabetes. Multiple studies have indicated that both white (WAT) and brown (BAT) adipose tissue may play an important role to mediate the beneficial effects of exercise. Studies from both rodents and humans have identified exercise-induced changes in WAT including increased mitochondrial activity and glucose uptake, an altered endocrine profile, and in rodents, a beiging of the WAT. Studies investigating the effects of exercise on BAT have resulted in conflicting data in terms of mitochondrial activity, glucose uptake, and thermogenic activity in rodents and humans, and remain an important area of investigation. This review discusses the exercise-induced adaptations to white and brown adipose tissue, distinguishing important differences between rodents and humans and highlighting the latest studies in the field and their implications., (Copyright © 2020 Vidal and Stanford.)

Objective: Poor maternal and paternal environments increase the risk for obesity and diabetes in offspring, whereas maternal and paternal exercise in mice can improve offspring metabolic health. We determined the effects of combined maternal and paternal exercise on offspring health and the effects of parental exercise on offspring pancreas phenotype, a major tissue regulating glucose homeostasis., Research Design and Methods: Breeders were high fat fed and housed±running wheels before breeding (males) and before and during gestation (females). Offspring groups were: both parents sedentary (Sed); maternal exercise only (Mat Ex); paternal exercise only (Pat Ex); and maternal+paternal exercise (Mat+Pat Ex). Offspring were sedentary, chow fed, and studied at weaning, 12, 20 and 52 weeks., Results: While there was no effect of parental exercise on glucose tolerance at younger ages, at 52 weeks, offspring of Mat Ex, Pat Ex and Mat+Pat Ex displayed lower glycemia and improved glucose tolerance. The greatest effects were in offspring from parents that both exercised (Mat+Pat Ex). Offspring from Mat Ex, Pat Ex, and Mat+Pat Ex had decreased beta cell size, whereas islet size and beta cell mass only decreased in Mat+Pat Ex offspring., Conclusions: Maternal and paternal exercise have additive effects to improve glucose tolerance in offspring as they age, accompanied by changes in the offspring endocrine pancreas. These findings have important implications for the prevention and treatment of type 2 diabetes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Studies have demonstrated that exposure to fine particulate matter (PM 2.5 ) is linked to cardiovascular disease (CVD), which is exacerbated in patients with pre-existing conditions such as obesity. In the present study, we examined cardiac function of obese mice exposed to PM 2.5 and determined if mild exercise affected cardiac function., Methods: Obese mice (ob/ob) (leptin deficient, C57BL/6J background) were exposed to either filtered air (FA) or PM 2.5 at an average concentration of 32 μg/m 3 for 6 h/day, 5 days/week for 9 months. Following exposure, mice were divided into four groups: (1) FA sedentary, (2) FA treadmill exercise, (3) PM 2.5 sedentary, and (4) PM 2.5 treadmill exercise and all mice were analyzed after 8 weeks of exercise training., Results: Echocardiography showed increased left ventricular end systolic (LVESd) and diastolic (LVEDd) diameters in PM 2.5 sedentary mice compared to FA sedentary mice. There was increased expression of ICAM1, VCAM and CRP markers in sedentary PM 2.5 mice compared to FA mice. Both FA and PM 2.5 exercised mice showed decreased posterior wall thickness in systole compared to FA sedentary mice, coupled with altered expression of inflammatory markers following exercise., Conclusion: Obese mice exposed to PM 2.5 for 9 months showed cardiac dysfunction, which was not improved following mild exercise training., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

Obesity is a disease that results from an imbalance between energy intake and energy expenditure. Brown adipose tissue (BAT) is a potential therapeutic target to improve the comorbidities associated with obesity due to its inherent thermogenic capacity and its ability to improve glucose metabolism. Multiple studies have shown that activation of BAT using either pharmacological treatments or cold exposure had an acute effect to increase metabolic function and reduce adiposity. Recent preclinical investigations have explored whether increasing BAT mass or activation through transplantation models could improve glucose metabolism and metabolic health. Successful BAT transplantation models have shown improvements in glucose metabolism and insulin sensitivity, as well as reductions in body mass and decreased adiposity in recipients. BAT transplantation may confer its beneficial effects through several different mechanisms, including endocrine effects via the release of 'batokines'. More recent studies have demonstrated that beige and brown adipocytes isolated from human progenitor cells and transplanted into mouse models result in metabolic improvements similar to transplantation of whole BAT; this could represent a clinically translatable model. In this review we will discuss the impetus for both early and recent investigations utilizing BAT transplantation models, the outcomes of these studies, and review the mechanisms associated with the beneficial effects of BAT transplant to confer improvements in metabolic health., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Obesity is a complex disease that affects whole body metabolism and is associated with an increased risk of cardiovascular disease (CVD) and Type 2 diabetes (T2D). Physical exercise results in numerous health benefits and is an important tool to combat obesity and its co-morbidities, including cardiovascular disease. Exercise prevents both the onset and development of cardiovascular disease and is an important therapeutic tool to improve outcomes for patients with cardiovascular disease. Some benefits of exercise include enhanced mitochondrial function, restoration and improvement of vasculature, and the release of myokines from skeletal muscle that preserve or augment cardiovascular function. In this review we will discuss the mechanisms through which exercise promotes cardiovascular health.

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.