UCP1-dependent brown adipose activation accelerates cardiac metabolic remodeling and reduces initial hypertrophic and fibrotic responses to pathological stress.

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 ß-MHC by 61% versus RT-TAC and reduced pro-fibrotic TGF-ß1 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.

Electronic Nicotine Delivery Systems and Cardiovascular/Cardiometabolic Health.

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 as a tool to mitigate metabolic disease.

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.

Hepatic protein kinase Cbeta deficiency mitigates late-onset obesity.

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 (PKCß) expression, while hepatocyte PKCß deficiency (PKCßHep-/-) in mice significantly attenuates obesity in aged mice fed a high-fat diet. Compared with control PKCßfl/fl mice, PKCßHep-/- mice showed elevated energy expenditure with augmentation of oxygen consumption and carbon dioxide production which was dependent on ß3-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 PKCßHep-/- mice, we determined that PKCß overexpression in the liver mitigated elevated expression of thermogenic genes in BAT. In conclusion, our study thus establishes hepatocyte PKCß 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.

Metabolic trade-offs in Neonatal sepsis triggered by TLR4 and TLR1/2 ligands result in unique dysfunctions in neural breathing circuits.

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.

Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25.

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.

The Heartwarming Effect of Brown Adipose Tissue.

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. ß-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.

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.

Differential Responses to Sigma-1 or Sigma-2 Receptor Ablation in Adiposity, Fat Oxidation, and Sexual Dimorphism.

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 O2 and CO2, 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.

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.

Exercise-induced adaptations to white and brown adipose tissue.

The beneficial effects of exercise on skeletal muscle and the cardiovascular system have long been known. Recent studies have focused on investigating the effects of exercise on adipose tissue and the effects that these exercise-induced adaptations have on overall metabolic health. Examination of exercise-induced adaptations in both white adipose tissue (WAT) and brown adipose tissue (BAT) has revealed marked differences in each tissue with exercise. In WAT, there are changes to both subcutaneous WAT (scWAT) and visceral WAT (vWAT), including decreased adipocyte size and lipid content, increased expression of metabolic genes, altered secretion of adipokines and increased mitochondrial activity. Adaptations specific to scWAT include lipidomic remodeling of phospholipids and, in rodents, the beiging of scWAT. The changes to BAT are less clear: studies evaluating the effect of exercise on the BAT of humans and rodents have revealed contradictory data, making this an important area of current investigation. In this Review, we discuss the exercise-induced changes to WAT and BAT that have been reported by different studies and highlight the current questions in this field.

Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice.

OBJECTIVE: Chylomicron and very low-density lipoprotein remnants are cleared from the circulation in the liver by heparan sulfate proteoglycan (HSPG) receptors (syndecan-1), the low-density lipoprotein receptor (LDLR), and LDLR-related protein-1 (LRP1), but the relative contribution of each class of receptors under different dietary conditions remains unclear. APPROACH AND RESULTS: Triglyceride-rich lipoprotein clearance was measured in AlbCre(+)Ndst1(f/f), Ldlr(-/-), and AlbCre(+)Lrp1(f/f) mice and mice containing combinations of these mutations. Triglyceride measurements in single and double mutant mice showed that HSPGs and LDLR dominate clearance under fasting conditions and postprandial conditions, but LRP1 contributes significantly when LDLR is absent. Mice lacking hepatic expression of all 3 receptors (AlbCre(+)Ndst1(f/f) Lrp1(f/f) Ldlr(-/-)) displayed dramatic hyperlipidemia (870 ± 270 mg triglyceride/dL; 1300 ± 350 mg of total cholesterol/dL) and exhibited persistent elevated postprandial triglyceride levels because of reduced hepatic clearance. Analysis of the particles accumulating in mutants showed that HSPGs preferentially clear a subset of small triglyceride-rich lipoproteins (≈ 20-40 nm diameter), whereas LDLR and LRP1 clear larger particles (≈ 40-60 nm diameter). Finally, we show that HSPGs play a major role in clearance of triglyceride-rich lipoproteins in mice fed normal chow or under postprandial conditions but seem to play a less significant role on a high-fat diet. CONCLUSIONS: These data show that HSPGs, LDLR, and LRP1 clear distinct subsets of particles, that HSPGs work independently of LDLR and LRP1, and that HSPGs, LDLR, and LRP1 are the 3 major hepatic triglyceride-rich lipoprotein clearance receptors in mice.

Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle.

Exercise is a well-established tool to prevent and combat type 2 diabetes. Exercise improves whole body metabolic health in people with type 2 diabetes, and adaptations to skeletal muscle are essential for this improvement. An acute bout of exercise increases skeletal muscle glucose uptake, while chronic exercise training improves mitochondrial function, increases mitochondrial biogenesis, and increases the expression of glucose transporter proteins and numerous metabolic genes. This review focuses on the molecular mechanisms that mediate the effects of exercise to increase glucose uptake in skeletal muscle.

Exercised breastmilk: a kick-start to prevent childhood obesity?

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.

Exercise training and cold exposure trigger distinct molecular adaptations to inguinal white adipose tissue.

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.

Contributions of mouse genetic strain background to age-related phenotypes in physically active HET3 mice.

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.

Maternal exercise preserves offspring cardiovascular health via oxidative regulation of the ryanodine receptor.

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.

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.