Biogenesis In Adipose Tissue Research Articles

Nicotinamide reprograms adipose cellular metabolism and increases mitochondrial biogenesis to ameliorate obesity

Obesity poses a global health challenge and is a major risk factor for diabetes mellitus, cardiovascular diseases, hypertension, stroke and certain kinds of cancers. Although the effects of nicotinamide (NAM) on liver metabolism and diseases were well documented, its effects on adipose tissue are yet to be characterized. Herein, we found that NAM supplementation significantly reduced fat mass and improved glucose tolerance in obese mice. Proteomic analysis revealed that NAM supplementation upregulates mitochondrial proteins while quantitative polymerase chain reaction showed that PPARα and PGC1α were both upregulated in adipose tissues, proposing that NAM increased mitochondrial biogenesis in adipose tissue. Indeed, NAM treatment increased proteins related to mitochondrial functions including oxidative phosphorylation, fatty acid oxidation, and TCA cycle. Furthermore, isotope-tracing assisted metabolic profiling revealed that NAM activated NAMPT and increased cellular NAD+ level by 30%. Unexpectedly, we found that NAM also increased glucose derived amino acids to enhance glutathione synthesis for maintaining cellular redox homeostasis. Taken together, our results demonstrated that NAM reprogramed cellular metabolism, enhanced adipose mitochondrial functions to ameliorate symptoms associated with obesity.

Adipocyte-Derived Exosomes Increase the Growth of Breast Tumors in Obese Mice

Abstract Objectives 1) We assessed whether the secretion and cargos of exosomes are distinct in obese and lean mice. 2) We assessed whether adipocyte-derived exosomes increase the size of tumors of the mammary gland in mice. Methods Female tamoxifen-inducible adipose-specific TSG101 conditional knockout mice (TSG KO) were initiated on an AIN-93G-based 50% high fat (HFD) or 15.8% low fat (LFD) at age 3 weeks and continued on these diets for 10 weeks. At age 4 weeks, mice were injected with tamoxifen or vehicle (TSG+), followed by the injection of 1.8*106 murine breast adenocarcinoma E0771 cells into the mammary gland fat pad 10 days after tamoxifen injection. Loss and gain of TSG101 and Cre, respectively, in inguinal subcutaneous adipose tissue were confirmed by RT-qPCR. Tumors were excised and their size was assessed using a caliper and by weight. H&E staining was used to assess the tumor type. Exosomes were isolated from plasma by an ExoQuick Plasma Prep kit, authenticated by western blot analysis and counted using a Nanosight tracker. The statistical analysis was performed by one-way ANOVA and Least Significant Differences posthoc test using a significance level of P < 0.05. Results HFD led to an increase in breast tumor size, which was diminished in adipose-specific TSG101 KO fed HFD: The size of mammary tumors in TSG+ fed HFD increased by 198% compared to TSG+ fed LFD (P < 0.05), whereas tumor size decreased by 58% TSG101 KO fed HFD compared to TSG+ fed HFD (P < 0.05). HFD led to an increase in adipose-derived exosomes that was reduced by TSG101 KO: The expression of ASC-1, a marker for adipose-derived exosomes in plasma exosomes increased by 58% in TSG+ fed HFD compared to TSG+ fed LFD, and decreased by 29% in TSG KO fed HFD compared to TSG+ fed HFD (P < 0.05). Plasma exosomes tested positive for exosome markers, CD63, CD81 and HSP70 and negative for a non-exosome marker, calnexin. H&E staining suggested that the tumors observed in all mice were adenocarcinomas. Tumor numbers were not affected by TSG101 and diet. Conclusions HFD increases the growth of mammary tumors in mice and the diet effect depends on exosome biogenesis in adipose tissue. We speculate that adipose-derived exosomes promote tumor growth but not metastasis. Funding Sources NIFA, NIH, and USDA. J.Z. is a consultant for PureTech Health.

Examining the effects of housing temperature on mitochondrial adaptations to exercise and the browning of white adipose tissue

The thermoneutral zone for small rodents is ~29–31°C and with decreases in ambient temperature below this there are consequent increases in metabolism to promote thermogenesis. Despite this, many studies report housing mice at room temperature for the convenience of the researchers studying them. As such, the conflicting reports between human and rodent models of exercise‐induced mitochondrial biogenesis in adipose tissue and the browning of white adipose tissue may be explained by the often‐overlooked variable, housing temperature. Male 8‐week‐old C57BL/6 mice were housed in cages with (VWR) or without (SED) running wheels (n = 12/group/condition) for 5–6 weeks at room temperature (RT; 22°C) or at thermoneutrality (TN; ~29°C). Mice housed at TN ran a greater distance. VWR protected against weight gain independent of housing temperature however food intake was greater in both VWR and SED mice housed at RT compared to TN. Inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) mass were reduced following VWR independent of housing temperature and there were main effects of both exercise and temperature to reduce brown adipose tissue (BAT) mass. There was no effect of housing temperature on circulating glucose or glycerol concentrations however NEFA, insulin, and the HOMA‐IR were increased at TN. In eWAT there was a main effect of exercise to increase cytochrome c oxidoreductase core I subunit (CORE1), cytochrome c oxidase, and peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) protein content with a main effect of housing temperature for PGC‐1α as well. There was a strong trend for an exercise‐induced increase in pyruvate dehydrogenase (PDH). In iWAT, there was a main effect of exercise and temperature on mitochondrial proteins with VWR leading to the expected increases in PDH, CORE1, COX IV, and PGC‐1α, but reduced markers of mitochondrial content at TN. Most notably protein content of the thermogenic uncoupling protein‐1 (UCP‐1) was undetectable in iWAT at TN. Qualitative histological analysis revealed patches of multilocular adipocytes in iWAT with VWR at RT but not at TN. Together our findings provide novel evidence that while housing mice at TN reduces markers of mitochondrial content in adipose tissue under sedentary conditions, the ability of exercise to increase mitochondrial protein content remains largely intact.Support or Funding InformationOntario Graduate Scholarship Canada Research Chairs ProgramThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Thermal stress induces glycolytic beige fat formation via a myogenic state.

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fiber-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evokes developmental plasticity remain insufficiently understood. Here, we report a previously uncharacterized form of beige adipocytes that play a critical role in cold adaptation in the absence of β-adrenergic receptor (β-AR) signaling. This unique beige fat possesses distinct characteristics from the conventional beige fat in their developmental origin, regulation, and enhanced glucose oxidation; hence, we refer to them as glycolytic beige fat (g-beige). Mechanistically, we identify GA-binding protein alpha (GABPα) that controls g-beige adipocyte differentiation through a myogenic intermediate. Our study uncovers a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cells required for energy homeostasis and survival.

Effect of increasing body condition on oxidative stress and mitochondrial biogenesis in subcutaneous adipose tissue depot of nonlactating dairy cows

With the onset of lactation, dairy cows with a body condition score >3.5 are sensitive to oxidative stress and metabolic disorders. Adipose tissue (AT) can adapt to varying metabolic demands and energy requirements by the plasticity of its size during lactation. In AT, angiogenesis is necessary to guarantee sufficient oxygen and nutrient supply for adipocytes. Cellular energy metabolism is reflected mainly by mitochondria, which can be quantified by the mitochondrial DNA copy number per cell. In the present study, we aimed to investigate the effect of overconditioning on angiogenesis and mitochondrial biogenesis in AT of nonlactating cows, irrespective of the physiological influences of lactation and pregnancy. Eight nonpregnant, nonlactating cows received a ration of increasing energy density for 15 wk, during which body weight and body condition increased substantially. Subcutaneous AT was biopsied every 8 wk, and blood was sampled monthly. The blood concentrations of indicators of oxidative stress increased continuously throughout the experimental period, possibly damaging mitochondrial DNA. Concomitantly, HIF-1α, a major marker for hypoxia, increased until wk 8, indicating insufficient angiogenesis in the rapidly expanding AT. Based on the observation that the number of apoptotic cells decreased with increasing hypoxia, the increasing mitochondrial DNA copy numbers might compensate for the hypoxia, reinforcing the production of oxidative stressors. Key transcription factors of mitochondrial biogenesis were largely unaffected. Thus, increased oxidative stress does not impair mitochondrial DNA.

Impaired Mitochondrial Biogenesis in Adipose Tissue in Acquired Obesity.

Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. However, the stage at which mitochondrial dysfunction manifests in adipose tissue after the onset of obesity remains unknown. Here we examined subcutaneous adipose tissue (SAT) samples from healthy monozygotic twin pairs, 22.8-36.2 years of age, who were discordant (ΔBMI >3 kg/m(2), mean length of discordance 6.3 ± 0.3 years, n = 26) and concordant (ΔBMI <3 kg/m(2), n = 14) for body weight, and assessed their detailed mitochondrial metabolic characteristics: mitochondrial-related transcriptomes with dysregulated pathways, mitochondrial DNA (mtDNA) amount, mtDNA-encoded transcripts, and mitochondrial oxidative phosphorylation (OXPHOS) protein levels. We report global expressional downregulation of mitochondrial oxidative pathways with concomitant downregulation of mtDNA amount, mtDNA-dependent translation system, and protein levels of the OXPHOS machinery in the obese compared with the lean co-twins. Pathway analysis indicated downshifting of fatty acid oxidation, ketone body production and breakdown, and the tricarboxylic acid cycle, which inversely correlated with adiposity, insulin resistance, and inflammatory cytokines. Our results suggest that mitochondrial biogenesis, oxidative metabolic pathways, and OXPHOS proteins in SAT are downregulated in acquired obesity, and are associated with metabolic disturbances already at the preclinical stage.

Biphasic Response of Mitochondrial Biogenesis to Oxidative Stress in Visceral Fat of Diet-Induced Obesity Mice

Studies in skeletal muscle demonstrate a strong association of mitochondrial dysfunction with insulin resistance (IR). However, there is still a paucity of knowledge regarding the alteration of mitochondria in adipose tissue (AT) in the pathogenesis of IR in obesity. We investigated the mitochondrial biogenesis in visceral fat (VF) and subcutaneous fat (SF) in C57BL/6J mice fed a high-fat high-sucrose diet for 12 months. Impairment of glucose tolerance and insulin sensitivity developed after 1 month of the diet and was associated with a prompt increase of VF. The VF adipocytes were larger than those in the SF and had increased expressions of HIF-1α and p-NFκB p65. However, the alteration of mitochondrial biogenesis did not occur in the early stage when increased intracellular reactive oxygen species (ROS), mitochondrial oxygen consumption rate, and mitochondrial ROS emerged at the 1st, 2nd and 2nd month, respectively. Until the 6th month, the VF had markedly increased mitochondrial DNA content and expression of PGC-1α, Tfam, ATP5A, and MnSOD. This increase of mitochondrial biogenesis was followed by a generalized decrease at the 12th month and the mitochondrial morphology altered markedly. In the late stage, although mitochondrial ROS decreased, the increased expression of 8-OHdG in VF continued. These data suggest that IR and ROS production occur before the biphasic changes of mitochondrial biogenesis in AT, and the VF plays a more crucial role.

Mitochondrial biogenesis in adipose tissue: can exercise make fat cells ‘fit’?

White adipose tissue (WAT) is now considered an active endocrine organ and its dysregulation predicts metabolic diseases. Much emphasis has recently been placed on the role of mitochondrial biogenesis in adipose tissue, since diabetic rodents, as well as overweight or obese humans with insulin resistance (IR), have reduced WAT mitochondrial content and function. Treatments that increase mitochondrial biogenesis in WAT could potentially improve IR and reduce obesity, making them a hot pursuit. Some pharmacological treatments including peroxisome proliferator-activated receptor γ (PPARγ) agonists (e.g. thiazolidinediones, TZDs) show promise in this area, but carry with them unfavourable side effects including weight gain, making behavioural interventions to improve WAT metabolic function an attractive alternative. Exercise training is known to increase mitochondrial biogenesis in skeletal muscle, but surprisingly little is known about the effect of exercise on mitochondrial biogenesis in WAT. In a recent article in The Journal of Physiology, Sutherland and colleagues examined the effect of both acute and chronic exercise on markers of mitochondrial biogenesis in WAT (Sutherland et al. 2009) and explored potential mechanisms by which exercise might exert these effects. Sutherland et al. exercise-trained male Wistar rats using swimming exercise (2 h day−1, 7 days week−1 for 4 weeks). To assess mitochondrial protein content, the respiratory chain complex proteins COXIV (cytochrome c oxidase subunit IV) and CORE1 (cytochrome c oxidoreductase core I subunit) were analysed. In addition, gene expression levels of PPARγ coactivator-1 (PCG-1α, a major regulator of mitochondrial biogenesis), and mitochondrial transcription factor A (Tfam, a transcription factor involved in mitochondrial biogenesis downstream of PGC-1α) were measured in WAT. Citrate synthase activity was measured to confirm that the increases in protein content and gene expression corresponded with increases in mitochondrial function.