Thermoneutrality Reduces the Beneficial Metabolic Effects of Eicosapentaenoic Acid on White Adipose Tissue in Diet-Induced Obese Mice

Abstract Objectives At ambient temperature (23°C), eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid reduces visceral adipose tissue (VAT) inflammation, adipocyte size and improves overall metabolic profile in diet-induced obese (DIO) mice, potentially through upregulation of uncoupling protein 1 (UCP-1). The goal of this study is to determine whether effects of EPA are maintained at thermoneutrality, and/or mediated by UCP-1, and if so through which cellular mechanisms. Methods Wild type (WT) and UCP-1 knockout (KO) B6 male mice were housed at thermoneutral temperature (28–30°C) and fed high fat (HF, 45% kcal fat) supplemented with or without EPA (36 g/kg diet). Serum, VAT (epididymal fat) and cecal microbiome specimens were analyzed. Results EPA reduced adiposity and improved glucose tolerance in EPA-fed KO mice (P < 0.05), but not in EPA-fed WT mice. EPA supplementation lowered VAT mass in both genotypes (P < 0.05); however, there were no diet or genotype-related differences in adipocyte size or serum triglyceride levels. Both genotypes fed EPA had lower serum resistin levels compared to respective HF (P < 0.01). EPA showed trends towards increased serum adiponectin levels compared to HF fed mice in both genotypes, with KO-EPA group having the highest concentration. There was no significant difference in the expression of IL-6 in VAT among the groups, while MCP-1 mRNA was expressed more in KO groups compared to WT groups (P < 0.01). Diet had no effect on expression of anti-inflammatory markers in both WT and KO mice. There were no genotype or diet effects on expression of genes involved in lipid metabolism and mitochondrial energy metabolism. Cecal microbiome showed no differences in the species diversity (Shannon index) between genotypes or diet types. However, only in the KO group, the Bacteroidetes/Firmicutes ratio was increased by EPA. Conclusions Compared to previous work at ambient temperatures, VAT does not mediate protective effects of EPA in DIO mice at thermoneutral temperature. Moreover, EPA effects are independent of UCP-1 as it produced beneficial effects on glucose tolerance and adiposity in KO mice, which may be in part mediated by changes in microbiome. Further mechanistic studies are ongoing to understand the mechanisms mediating EPA and UCP-1 effects in VAT. Funding Sources Funded by NIH (NCCIH and NIA).

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Temperature-Dependent Effects of Eicosapentaenoic Acid on Browning of Subcutaneous Adipose Tissue From UCP1 Knockout Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzab055_072 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 1262-1262

Author(s):

Yujiao Zu ◽

Mandana Pahlavani ◽

Latha Ramalingam ◽

Shane Scoggin ◽

Naima Moustaid-Moussa

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Glucose Tolerance ◽

Eicosapentaenoic Acid ◽

Ambient Temperature ◽

Subcutaneous Adipose Tissue ◽

Brown Fat ◽

Metabolic Effects ◽

Diet Induced Obesity ◽

Subcutaneous Adipose

Abstract Objectives Activation and recruitment of thermogenic cells in white adipose tissue (WAT browning), in response to cold exposure, can combat obesity and associated metabolic disorders. We have previously reported that the beneficial effects of eicosapentaenoic acid (EPA), a long-chain omega 3 polyunsaturated fatty acids, in obesity and insulin resistance are independent of UCP1. In this study, we investigate the protective effects of EPA and the role of UCP1 in the browning of subcutaneous adipose tissue (SAT) at ambient and thermoneutral environments using UCP1 knockout (KO) mice. We hypothesized that EPA promotes SAT browning to prevent diet-induced obesity at both temperatures, independently of UCP1. Methods Male and UCP1 KO and wild type (WT) B6 littermates were housed at room temperature (22°C) or thermoneutrality (28–30°C) and fed a high fat (HF) diet (45% kcal fat) supplemented with or without EPA (36g/kg) for 14 weeks. Body weight and glucose tolerance test (GTT) were measured, and browning-related markers were assessed in SAT. Data were statistically analyzed via three-way ANOVA using GraphPad to determine the individual and interactive effects of temperature, genotype, and diet. Results Compared to the WT, the body weight (BW) of KO mice increased at thermoneutrality (P < 0.01) but decreased at ambient temperature (P < 0.0001). Additionally, EPA attenuated weight and fat mass gain at thermoneutrality and improved glucose tolerance at both temperatures in both genotypes. mRNA levels for brown fat markers (Dio2 and Cidea), lipid metabolism (Elovl3, PGC1α, FASN, Cpt1b, and Gpd1), and batokines (Bmp8b and FGF21) were significantly up-regulated in KO mice, compared to WT, at ambient temperature (P < 0.01). Moreover, compared to HF-fed mice, EPA increased above markers in the KO mice at ambient temperature. Compared to HF, EPA-fed mice had significantly higher serum adiponectin levels (P < 0.01) in both genotypes and temperatures. Conclusions UCP1 KO male mice were protected from diet-induced obesity and glucose intolerance and had increased SAT browning at ambient temperature. These results indicate that alternative thermoregulatory pathways mediate protective metabolic effects of EPA, in the absence of UCP1. These findings may be translated to human subjects with obesity, who exhibit low amounts of brown fat and UCP1. Funding Sources NIH R15AT008879-01A1.

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Metabolic Effects of Eicosapentaenoic Acid in the APPswePS1dE9 Alzheimer's Mouse Model

Current Developments in Nutrition ◽

10.1093/cdn/nzaa057_058 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1242-1242

Author(s):

Mahsa Yavari ◽

Latha Ramalingam ◽

Breanna Harris ◽

Shane Scoggin ◽

Caroline Biltz ◽

...

Keyword(s):

Glucose Tolerance ◽

Mouse Model ◽

Eicosapentaenoic Acid ◽

Fat Mass ◽

Neurodegenerative Disorder ◽

Metabolic Effects ◽

Omega 3 ◽

High Fat ◽

Lower Glucose ◽

Glucose Clearance

Abstract Objectives Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by presence of amyloid plaques. Exact etiology treatment and early diagnosis is still unknown and not possible. Obesity is an important risk factor of neurodegenerative disorders. Eicosapentaenoic acid (EPA), a long-chain omega-3 polyunsaturated fatty acid exerts anti-inflammatory effects, but how EPA affects AD is unknown. This study aims to determine whether EPA supplementation improves overall metabolic status in transgenic APPswePS1E9 mouse model. Methods Mice were sexed, transgenic (Tg) and wild type (Wt), randomly assigned at 2 months of age to a diet treatment: low fat (LF), high fat (HF), or high fat with EPA (HF-EPA), with 10–12 mice per diet for each sex and genotype. Weekly, body weight (BW) and food intake were recorded. Body composition (BC) conducted every 2 months and glucose tolerance tests were conducted at 5 months. At 10 months, mice were euthanized, and tissues and serum were collected. Results Differences in BW among groups were observed from 8 months and results differed by sex and genotype (P < 0.05). In male mice, diet did not affect BW in Wt group, but Tg males fed HF had significantly higher BW than LF Tg, with no difference between HF and HF-EPA. Among female mice, HF groups (HF or HF-EPA) in both genotypes were significantly heavier than those fed LF, while HF and HF-EPA did not differ. Fat mass measured during the 4th and 6th month in males was significantly higher in all HF groups compared to LF genotypes. However, at 10th month, fat mass was higher only in HF mice of both genotypes in comparison with LF, with no difference between HF or HF-EPA groups. In females, only HF-EPA fed mice had higher fat mass than LF genotypes at 10 months. In males, no difference was observed in glucose clearance among Wt mice, regardless of the diet. However, only male HF-Tg mice had lower glucose clearance compared to LF genotypes, while HF and HF-EPA were comparable. In females, HF-EPA Tg mice had lower glucose clearance compared to LF and HF Tg mice. Conclusions These findings indicate that HF diet induced sex-independent metabolic dysfunction in both Wt and Tg mice. However, EPA did not exert any metabolic effects based on BW, glucose tolerance and adiposity. Further tissue-specific analyses are ongoing to understand the basis for these diet, sex and genotype differences. Funding Sources NIH (NCCIH and NIA).

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Eicosapentaenoic Acid Increases Browning Markers in Subcutaneous Adipose Tissue and Primary Adipocytes from Wild Type and UCP-1 Deficient Mice (P15-007-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz037.p15-007-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Shasika Jayarathne ◽

Mandana Pahlavani ◽

Latha Ramalingam ◽

Shane Scoggin ◽

Naima Moustaid-Moussa

Keyword(s):

Adipose Tissue ◽

Eicosapentaenoic Acid ◽

Subcutaneous Adipose Tissue ◽

Uncoupling Protein ◽

Fibroblast Growth Factor 21 ◽

Chow Diet ◽

Mrna Levels ◽

Wild Type ◽

Brown Adipose ◽

Subcutaneous Adipose

Abstract Objectives Brown adipose tissue (BAT) regulates energy balance through thermogenesis, in part via uncoupling protein -1 (UCP-1). White adipose tissue (WAT), namely subcutaneous adipose tissue (SAT) can convert to a beige/brite adipose tissue phenotype (browning) under thermogenic conditions such as cold. We previously reported that eicosapentaenoic acid (EPA) reduced obesity and glucose intolerance, and increased UCP-1 in BAT of B6 mice at ambient temperature (22°C); and these effects were attenuated at thermoneutral environment (28–30°C). We hypothesized that EPA exerts anti-obesity effects on SAT, including increased browning, adipocyte hypotrophy; and these effects require UCP-1. Methods Six-week-old B6 wild type (WT) and UCP-1 knock-out (KO) male mice were maintained at thermoneutral environment and fed high fat diet (HF) with or without 36 g/kg of AlaskOmega EPA-enriched fish oil (800 mg/g) for 14 weeks; and SAT was collected for histological, gene and protein analyses. SAT was also prepared from chow diet-fed WT and KO mice at ambient environment to prepare stroma vascular cells, which were differentiated into adipocytes, treated with 100uM EPA for 48 hours then harvested for mRNA and protein analyses. Results KO mice fed HF diets had the highest body weight (P < 0.05) among all groups. EPA reduced fat cell size in both WT and KO mice fed the EPA diet. mRNA levels of fibroblast growth factor-21 (FGF-21) were higher in SAT of WT mice fed EPA compared to WT mice fed HF (P < 0.05), with no differences between the KO genotype. KO mice fed HF diets had lower levels of UCP-3 in SAT compared to WT mice fed HF (P < 0.05), which was rescued only in the KO mice fed EPA (P < 0.05). UCP-1 protein levels were very low in SAT tissues, and UCP-2 mRNA levels were similar across all groups in SAT. Interestingly, EPA significantly (P < 0.05) increased mRNA expression of UCP-2, UCP-3 and FGF21 in differentiated SAT adipocytes from both WT and KO compared to control. Furthermore, UCP-1 mRNA levels were significantly higher in WT adipocytes treated with EPA, compared to non-treated cells (P < 0.05). Additional mechanistic studies are currently underway to further dissect adipose depot differences in EPA effects in WT vs. KO mice. Conclusions Our data suggest that EPA increases SAT browning, independently of UCP-1. Funding Sources NIH/NCCIH.

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Metabolic Effects of Oral Phenelzine Treatment on High-Sucrose-Drinking Mice

International Journal of Molecular Sciences ◽

10.3390/ijms19102904 ◽

2018 ◽

Vol 19 (10) ◽

pp. 2904 ◽

Cited By ~ 5

Author(s):

Christian Carpéné ◽

Saioa Gómez-Zorita ◽

Alice Chaplin ◽

Josep Mercader

Keyword(s):

Adipose Tissue ◽

Phosphoenolpyruvate Carboxykinase ◽

De Novo ◽

Uncoupling Protein ◽

De Novo Lipogenesis ◽

Metabolic Effects ◽

Mrna Levels ◽

Brown Adipose ◽

High Sucrose ◽

Sucrose Drinking

Phenelzine has been suggested to have an antiobesity effect by inhibiting de novo lipogenesis, which led us to investigate the metabolic effects of oral chronic phenelzine treatment in high-sucrose-drinking mice. Sucrose-drinking mice presented higher body weight gain and adiposity versus controls. Phenelzine addition did not decrease such parameters, even though fat pad lipid content and weights were not different from controls. In visceral adipocytes, phenelzine did not impair insulin-stimulated de novo lipogenesis and had no effect on lipolysis. However, phenelzine reduced the mRNA levels of glucose transporters 1 and 4 and phosphoenolpyruvate carboxykinase in inguinal white adipose tissue (iWAT), and altered circulating levels of free fatty acids (FFA) and glycerol. Interestingly, glycemia was restored in phenelzine-treated mice, which also had higher insulinaemia. Phenelzine-treated mice presented higher rectal temperature, which was associated to reduced mRNA levels of uncoupling protein 1 in brown adipose tissue. Furthermore, unlike sucrose-drinking mice, hepatic malondialdehyde levels were not altered. In conclusion, although de novo lipogenesis was not inhibited by phenelzine, the data suggest that the ability to re-esterify FFA is impaired in iWAT. Moreover, the effects on glucose homeostasis and oxidative stress suggest that phenelzine could alleviate obesity-related alterations and deserves further investigation in obesity models.

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45 Unravelling the Unique Burn-induced Temporal Alterations in Adipose Tissue Metabolism

Journal of Burn Care & Research ◽

10.1093/jbcr/iraa024.049 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

pp. S30-S30

Author(s):

Carly M Knuth ◽

Chris Auger ◽

Abdikarim Abdullahi ◽

Marc G Jeschke

Keyword(s):

Adipose Tissue ◽

Murine Model ◽

Burn Injury ◽

Total Body Surface Area ◽

Time Dependent ◽

Metabolic Effects ◽

Whole Body ◽

Potential Contribution ◽

Significant Difference ◽

Tissue Browning

Abstract Introduction A severe burn elicits a systemic hypermetabolic response that substantially alters the function of multiple organs and contributes to increased morbidity and mortality. A consequence of hypermetabolism is the activation of UCP1-mediated browning of white adipose tissue (WAT), which may further facilitate the hypermetabolic response. In this study, we aimed to provide comprehensive characterization of the acute and long term pathophysiological responses to burns to determine the persistence of adipose tissue browning and its potential contribution to the hypermetabolic response. Methods Mice were subjected to either a 30% total body surface area (TBSA) scald burn or were denoted sham. Body weight and food intake were monitored throughout the duration of the study. Cohorts were sacrificed at 6hrs, 1, 3, 5, 7, 14, 30 and 60d post-burn and adipose tissue depots were harvested. Mitochondrial respiration, protein expression, and morphology in adipose tissues were assessed. Results Despite consuming considerably more food, the burn group lost significantly more weight throughout the duration of the study. We also detected increases in free fatty acids and interleukin-6, markers of whole-body lipolysis and inflammation, respectively. At the tissue level, eWAT mass significantly decreased over time, suggesting that this depot provides substrate to fuel the hypermetabolic response. This was further supported by a decrease in adipocyte area and an increase in lipolytic markers which remains significant up until 60d post-burn relative to sham. There were no significant difference in iWAT mass, however we detected significant increases in the protein content of UCP1, the master regulator of adipose tissue browning, as early as day 3 which persisted until day 60. This was corroborated by the presence of UCP1+ adipocytes. Conclusions Consistent with previous human studies, a burn injury elicits a dynamic response that cannot be simply characterized by a single timepoint. The alterations that occur in adipose tissue are depot-specific, time-dependent, and this notion likely extends to other metabolic tissues. Further, we demonstrate that in our 30% TBSA burn murine model, the effects of the hypermetabolic response persist for up to 60 days following initial injury. Applicability of Research to Practice Our data indicate the hypermetabolic response persists for up to 60 days, the equivalent of approximately 7 years in humans. This underscores the severity of adipose tissue browning and potentially provides an explanation as to how the hypermetabolic response persists even after the wound has healed. Moreover, providing a comprehensive map of the time-dependent changes in a murine model gives clinicians a better indication of the metabolic effects in a burn patient and will contribute to the development of effective, targeted treatments.

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46 Inhibition of Lipolysis with Acipimox Targets Post-burn White Adipose Browning by Altering Macrophage Polarity

Journal of Burn Care & Research ◽

10.1093/jbcr/iraa024.050 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

pp. S30-S31

Author(s):

Dalia Barayan ◽

Roohi Vinaik ◽

Marc G Jeschke

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Polarization State ◽

Critical Role ◽

Metabolic Effects ◽

Inhibitory Effects ◽

Macrophage Recruitment ◽

M2 Polarization ◽

Brown Adipose ◽

Major Burn

Abstract Introduction Severe burns are accompanied by a detrimental hypermetabolic stress response that can persist for years post-injury. Our previous work revealed that, under prolonged stress, white adipose tissue (WAT) adopts brown adipose-like traits in a process termed ‘browning’. This switch, characterized by the presence of uncoupling protein 1 (UCP1), is driven by the polarization of macrophages towards an M2 phenotype. Recently, we demonstrated that inhibiting lipolysis with the clinically approved drug, Acipimox, represses the burn-induced thermogenic activation of WAT. These findings raise the possibility that elevated rates of lipolysis may play a role in regulating the macrophage polarization state after major burn. However, the interconnection between post-burn lipolysis and inflammation remains unclear. In the present study, we investigated the mechanism underlying Acipimox’s inhibitory effects on burn-induced browning. Using a mouse model of thermal injury, we determine the metabolic effects of reducing WAT lipolysis on burn-induced macrophage recruitment and M2-polarization. Methods Adult C57BL/6 mice received a 30% total body surface area scald burn. Mice were then given daily intraperitoneal injections of APX (50 mg/Kg). On day 7 post-burn, the inguinal adipose tissue depot (iWAT) was harvested for histological analyses. Flow cytometry and F4/80 staining were used to assess adipose macrophage distribution and profile, and gene expression was analyzed via qPCR. Results APX administration significantly increased mitochondrial coupling, reflected by the decrease in UCP-1 (p< 0.05) and PGC-1a (p< 0.01) levels relative to the iWAT of untreated burn mice. F4/80 immunostaining of iWAT demonstrated decreased macrophage recruitment in Acipimox treated mice (p< 0.05). Flow cytometric analysis indicated decreased macrophage infiltration at 7 days in Acipimox treated mice (p< 0.05). Furthermore, iWAT from Acipimox treated mice demonstrated a pro-inflammatory profile, indicated by a greater distribution of TLR4 positive macrophages (p< 0.05). Conclusions Previously, we showed that the administration of Acipimox effectively suppressed PKA-mediated lipolysis and improved mitochondrial coupling in adipose tissue post-burn. Here, we elucidate the mechanism underlying these metabolic changes. Importantly, we show Acipimox exerts its inhibitory effects on burn-induced WAT browning by directly modulating macrophage recruitment and the M2-polarization state. Applicability of Research to Practice Our study highlights the critical role of lipolysis in mediating the key post-burn metabolic phenomena browning and inflammation. The data presented herein validate the pharmacological inhibition of lipolysis as a potentially powerful therapeutic strategy to counteract the detrimental metabolic effects induced by burn.

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Protective Effects of Eicosapentaenoic Acid Plus Hydroxytyrosol Supplementation Against White Adipose Tissue Abnormalities in Mice Fed a High-Fat Diet

Molecules ◽

10.3390/molecules25194433 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4433

Author(s):

Paola Illesca ◽

Rodrigo Valenzuela ◽

Alejandra Espinosa ◽

Francisca Echeverría ◽

Sandra Soto-Alarcon ◽

...

Keyword(s):

Adipose Tissue ◽

Eicosapentaenoic Acid ◽

White Adipose Tissue ◽

High Fat Diet ◽

Enzyme Linked Immunosorbent Assay ◽

Related Factor ◽

Nuclear Factor ◽

High Fat ◽

Mitochondrial Energy Metabolism ◽

Ppar Γ

Objective: Obesity induced by high-fat diet (HFD) elicits white adipose tissue dysfunction. In this study, we have hypothesized that the metabolic modulator eicosapentaenoic acid (EPA) combined with the antioxidant hydroxytyrosol (HT) attenuates HFD-induced white adipose tissue (WAT) alterations. Methods: C57BL/6J mice were administered with a HFD (60% fat, 20% protein, 20% carbohydrates) or control diet (CD; 10% fat, 20% protein, 70% carbohydrates), with or without EPA (50 mg/kg/day), HT (5 mg/kg/day), or both for 12 weeks. Determinations in WAT include morphological parameters, EPA and docosahexaenoic acid content in phospholipids (gas chromatography), lipogenesis, oxidative stress (OS) and inflammation markers, and gene expression and activities of transcription factors, such as sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor-gamma (PPAR-γ), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (p65 subunit) and nuclear factor erythroid 2-related factor 2 (Nrf2) (quantitative polymerase chain reaction and enzyme linked immunosorbent assay). Results: HFD led to WAT hypertrophy in relation to PPAR-γ downregulation. WAT metabolic dysfunction was characterized by upregulation of lipogenic SREBP-1c system, mitochondrial energy metabolism depression, loss of the antioxidant Nrf2 signaling with OS enhancement, n-3 long-chain polyunsaturated fatty acids depletion and activation of the pro-inflammatory NF-κB system. EPA and HT co-supplementation diminished HFD-dependent effects additively, reaching values close or similar to controls. Conclusion: Data presented strengthen the importance of combined protocols such as EPA plus HT to attenuate metabolic-inflammatory states triggered by obesity.

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Minor role of mature adipocyte mineralocorticoid receptor in high-fat diet-induced obesity

Journal of Endocrinology ◽

10.1530/joe-18-0314 ◽

2018 ◽

Vol 239 (2) ◽

pp. 229-240 ◽

Cited By ~ 4

Author(s):

A Feraco ◽

A Armani ◽

R Urbanet ◽

A Nguyen Dinh Cat ◽

V Marzolla ◽

...

Keyword(s):

Adipose Tissue ◽

Mouse Model ◽

High Fat Diet ◽

Mineralocorticoid Receptor ◽

Metabolic Effects ◽

Minor Role ◽

High Fat ◽

Mature Adipocyte ◽

Diet Induced Obesity ◽

Significant Difference

Obesity is a major risk factor that contributes to the development of cardiovascular disease and type 2 diabetes. Mineralocorticoid receptor (MR) expression is increased in the adipose tissue of obese patients and several studies provide evidence that MR pharmacological antagonism improves glucose metabolism in genetic and diet-induced mouse models of obesity. In order to investigate whether the lack of adipocyte MR is sufficient to explain these beneficial metabolic effects, we generated a mouse model with inducible adipocyte-specific deletion of Nr3c2 gene encoding MR (adipo-MRKO). We observed a significant, yet not complete, reduction of Nr3c2 transcript and MR protein expression in subcutaneous and visceral adipose depots of adipo-MRKO mice. Notably, only mature adipocyte fraction lacks MR, whereas the stromal vascular fraction maintains normal MR expression in our mouse model. Adipo-MRKO mice fed a 45% high-fat diet for 14 weeks did not show any significant difference in body weight and fat mass compared to control littermates. Glucose and insulin tolerance tests revealed that mature adipocyte MR deficiency did not improve insulin sensitivity in response to a metabolic homeostatic challenge. Accordingly, no significant changes were observed in gene expression profile of adipogenic and inflammatory markers in adipose tissue of adipo-MRKO mice. Moreover, pharmacological MR antagonism in mature primary murine adipocytes, which differentiated ex vivo from WT mice, did not display any effect on adipokine expression. Taken together, these data demonstrate that the depletion of MR in mature adipocytes displays a minor role in diet-induced obesity and metabolic dysfunctions.

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Genetic and Pharmacological Inhibition of PAPP-A Protects Against Visceral Obesity in Mice

Endocrinology ◽

10.1210/endocr/bqaa160 ◽

2020 ◽

Vol 161 (10) ◽

Author(s):

Akhila Ramakrishna ◽

Laurie K Bale ◽

Sally A West ◽

Cheryl A Conover

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Liver Lipid ◽

Protein A ◽

Visceral Obesity ◽

Cell Number ◽

Metabolic Effects ◽

Adipocyte Size ◽

Fat Depots ◽

Mesenteric Fat

Abstract Pathogenicity of visceral adipose tissue (VAT) has been linked to the metabolic stress of enlarging mature adipocytes and a limited ability to recruit new adipocytes. One of the major distinguishing features of VAT preadipocytes is the high expression of the zinc metalloprotease, pregnancy-associated plasma protein-A (PAPP-A), when compared to subcutaneous adipose tissue (SAT). In this study we used 2 different approaches to investigate the effect of PAPP-A inhibition on different fat depots in mice on a high-fat diet (HFD) for 15 weeks. Conditional knockdown of PAPP-A gene expression in female adult mice resulted in significant decreases of 30% to 40% in adipocyte size in VAT (mesenteric and pericardial depots) compared to control mice. There was no effect on SAT (inguinal) or intra-abdominal perigonadal fat. Liver lipid was also significantly decreased without any effect on heart and skeletal muscle lipid. We found similar effects when using a pharmacological approach. Weekly injections of a specific immunoneutralizing monoclonal antibody (mAb-PA 1/41) or isotype control were given to male and female wild-type mice on HFD for 15 weeks. Adipocyte size was significantly decreased (30%-50%) only in VAT with mAb-PA 1/41 treatment. In this model, cell number was significantly increased in mesenteric fat in mice treated with mAb-PA 1/41, suggesting hyperplasia along with reduced hypertrophy in this VAT depot. Gene expression data indicated a significant decrease in F4/80 (macrophage marker) and interleukin-6 (proinflammatory cytokine) and a significant increase in adiponectin (anti-inflammatory adipokine with beneficial metabolic effects) in mesenteric fat compared to inguinal fat in mice treated with mAb-PA 1/41. Furthermore, there was significantly decreased liver lipid content with mAb-PA 1/41 treatment. Thus, using 2 different models systems we provide proof of principle that PAPP-A inhibition is a potential therapeutic target to prevent visceral obesity and its metabolic sequelae, such as fatty liver.

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Plasma Docosahexaenoic Acid and Eicosapentaenoic Acid Concentrations Are Positively Associated with Brown Adipose Tissue Activity in Humans

Metabolites ◽

10.3390/metabo10100388 ◽

2020 ◽

Vol 10 (10) ◽

pp. 388

Author(s):

Angie S. Xiang ◽

Corey Giles ◽

Rebecca K.C. Loh ◽

Melissa F. Formosa ◽

Nina Eikelis ◽

...

Keyword(s):

Adipose Tissue ◽

Docosahexaenoic Acid ◽

Eicosapentaenoic Acid ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

Surrogate Marker ◽

Omega 3 ◽

Bat Activity ◽

Brown Adipose ◽

Lipid Species

Brown adipose tissue (BAT) activation is a possible therapeutic strategy to increase energy expenditure and improve metabolic homeostasis in obesity. Recent studies have revealed novel interactions between BAT and circulating lipid species—in particular, the non-esterified fatty acid (NEFA) and oxylipin lipid classes. This study aimed to identify individual lipid species that may be associated with cold-stimulated BAT activity in humans. A panel of 44 NEFA and 41 oxylipin species were measured using mass-spectrometry-based lipidomics in the plasma of fourteen healthy male participants before and after 90 min of mild cold exposure. Lipid measures were correlated with BAT activity measured via 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), along with norepinephrine (NE) concentration (a surrogate marker of sympathetic activity). The study identified a significant increase in total NEFA concentration following cold exposure that was positively associated with NE concentration change. Individually, 33 NEFA and 11 oxylipin species increased significantly in response to cold exposure. The concentration of the omega-3 NEFA, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) at baseline was significantly associated with BAT activity, and the cold-induced change in 18 NEFA species was significantly associated with BAT activity. No significant associations were identified between BAT activity and oxylipins.

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