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High CD8 T-Cell Receptor Clonality and Altered CDR3 Properties Are Associated With Elevated Isolevuglandins in Adipose Tissue During Diet-Induced Obesity.
McDonnell WJ, Koethe JR, Mallal SA, Pilkinton MA, Kirabo A, Ameka MK, Cottam MA, Hasty AH, Kennedy AJ
(2018) Diabetes 67: 2361-2376
MeSH Terms: Adipose Tissue, Animals, CD8-Positive T-Lymphocytes, Complementarity Determining Regions, Diet, High-Fat, Glucose Tolerance Test, Insulin Resistance, Liver, Male, Mice, Obesity, Prostaglandins
Show Abstract · Added March 26, 2019
Adipose tissue (AT) CD4 and CD8 T cells contribute to obesity-associated insulin resistance. Prior studies identified conserved T-cell receptor (TCR) chain families in obese AT, but the presence and clonal expansion of specific TCR sequences in obesity has not been assessed. We characterized AT and liver CD8 and CD4 TCR repertoires of mice fed a low-fat diet (LFD) and high-fat diet (HFD) using deep sequencing of the TCRβ chain to quantify clonal expansion, gene usage, and CDR3 sequence. In AT CD8 T cells, HFD reduced TCR diversity, increased the prevalence of public TCR clonotypes, and selected for TCR CDR3 regions enriched in positively charged and less polarized amino acids. Although TCR repertoire alone could distinguish between LFD- and HFD-fed mice, these properties of the CDR3 region of AT CD8 T cells from HFD-fed mice led us to examine the role of negatively charged and nonpolar isolevuglandin (isoLG) adduct-containing antigen-presenting cells within AT. IsoLG-adducted protein species were significantly higher in AT macrophages of HFD-fed mice; isoLGs were elevated in M2-polarized macrophages, promoting CD8 T-cell activation. Our findings demonstrate that clonal TCR expansion that favors positively charged CDR3s accompanies HFD-induced obesity, which may be an antigen-driven response to isoLG accumulation in macrophages.
© 2018 by the American Diabetes Association.
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MFe adipose tissue macrophages compensate for tissue iron perturbations in mice.
Hubler MJ, Erikson KM, Kennedy AJ, Hasty AH
(2018) Am J Physiol Cell Physiol 315: C319-C329
MeSH Terms: Adipocytes, Adipose Tissue, Animals, Cell Line, Dietary Supplements, Inflammation, Iron Overload, Iron, Dietary, Macrophages, Male, Mice, Mice, Inbred C57BL, Monocytes
Show Abstract · Added March 26, 2019
Resident adipose tissue macrophages (ATMs) play multiple roles to maintain tissue homeostasis, such as removing excess free fatty acids and regulation of the extracellular matrix. The phagocytic nature and oxidative resiliency of macrophages not only allows them to function as innate immune cells but also to respond to specific tissue needs, such as iron homeostasis. MFe ATMs are a subtype of resident ATMs that we recently identified to have twice the intracellular iron content as other ATMs and elevated expression of iron-handling genes. Although studies have demonstrated that iron homeostasis is important for adipocyte health, little is known about how MFe ATMs may respond to and influence adipose tissue iron availability. Two methodologies were used to address this question: dietary iron supplementation and intraperitoneal iron injection. Upon exposure to high dietary iron, MFe ATMs accumulated excess iron, whereas the iron content of MFe ATMs and adipocytes remained unchanged. In this model of chronic iron excess, MFe ATMs exhibited increased expression of genes involved in iron storage. In the injection model, MFe ATMs incorporated high levels of iron, and adipocytes were spared iron overload. This acute model of iron overload was associated with increased numbers of MFe ATMs; 17% could be attributed to monocyte recruitment and 83% to MFe ATM incorporation into the MFe pool. The MFe ATM population maintained its low inflammatory profile and iron-cycling expression profile. These studies expand the field's understanding of ATMs and confirm that they can respond as a tissue iron sink in models of iron overload.
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13 MeSH Terms
Cardiac natriuretic peptides promote adipose 'browning' through mTOR complex-1.
Liu D, Ceddia RP, Collins S
(2018) Mol Metab 9: 192-198
MeSH Terms: Adipose Tissue, Brown, Animals, Atrial Natriuretic Factor, Cells, Cultured, Cyclic GMP-Dependent Protein Kinases, Female, HEK293 Cells, Humans, Male, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Mitochondria, Signal Transduction, Uncoupling Protein 1
Show Abstract · Added September 25, 2018
OBJECTIVE - Activation of thermogenesis in brown adipose tissue (BAT) and the ability to increase uncoupling protein 1 (UCP1) levels and mitochondrial biogenesis in white fat (termed 'browning'), has great therapeutic potential to treat obesity and its comorbidities because of the net increase in energy expenditure. β-adrenergic-cAMP-PKA signaling has long been known to regulate these processes. Recently PKA-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) was shown to be necessary for adipose 'browning' as well as proper development of the interscapular BAT. In addition to cAMP-PKA signaling pathways, cGMP-PKG signaling also promotes this browning process; however, it is unclear whether or not mTORC1 is also necessary for cGMP-PKG induced browning.
METHOD - Activation of mTORC1 by natriuretic peptides (NP), which bind to and activate the membrane-bound guanylyl cyclase, NP receptor A (NPRA), was assessed in mouse and human adipocytes in vitro and mouse adipose tissue in vivo.
RESULTS - Activation of mTORC1 by NP-cGMP signaling was observed in both mouse and human adipocytes. We show that NP-NPRA-PKG signaling activate mTORC1 by direct PKG phosphorylation of Raptor at Serine 791. Administration of B-type natriuretic peptide (BNP) to mice induced Ucp1 expression in inguinal adipose tissue in vivo, which was completely blocked by the mTORC1 inhibitor rapamycin.
CONCLUSION - Our results demonstrate that NP-cGMP signaling activates mTORC1 via PKG, which is a component in the mechanism of adipose browning.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
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15 MeSH Terms
Balanced high fat diet reduces cardiovascular risk in obese women although changes in adipose tissue, lipoproteins, and insulin resistance differ by race.
Niswender KD, Fazio S, Gower BA, Silver HJ
(2018) Metabolism 82: 125-134
MeSH Terms: Adipose Tissue, Adult, African Continental Ancestry Group, Cardiovascular Diseases, Diet, High-Fat, European Continental Ancestry Group, Female, Humans, Insulin Resistance, Lipoproteins, Middle Aged, Obesity, Risk Factors, Young Adult
Show Abstract · Added April 10, 2018
BACKGROUND - We previously reported that consuming a balanced high fat diet (BHFD) wherein total saturated fat was reduced and total unsaturated fat increased by proportionately balancing the type of fat (1/3 saturated, 1/3 monounsaturated, 1/3 polyunsaturated) led to significant improvements in inflammatory burden, blood pressure, and vascular function in obese premenopausal European American (EA) and African American (AA) women.
OBJECTIVE - Here we compared changes in adipose tissue, lipoproteins, insulin resistance, and cardiovascular risk between EA and AA women.
METHODS - Dietary intakes, plasma fatty acids, lipids, apolipoproteins, lipoproteins, HOMA-IR and ASCVD risk was measured in 144 women who consumed BHFD for 16 weeks. Generalized linear modeling was performed while controlling for change in body weight.
RESULTS - EA women had greater reductions in visceral adipose tissue. Only EA women had significant reductions in fasting insulin levels (↓24.8%) and HOMA-IR (↓29%) scores. In EA women, the most significant improvements occurred in VLDL particle size (↑), apolipoprotein B levels (↑), serum TG (↓), number of plasma LDL particles (↓), and serum LDL-cholesterol (↓). In AA women, significant improvements occurred in HDL particle size (↑), number of large HDL particles (↑), and apolipoprotein AI levels (↑). Consequently, both groups had improved ASCVD risk scores (↓5.5%).
CONCLUSIONS - Consuming the balanced high fat diet led to significant reduction in cardiovascular risk factors in both groups. However, the pattern of response to BHFD differed with EA women responding more in components of the apolipoprotein B pathway versus AA women responding more in components of the apolipoprotein AI pathway.
Published by Elsevier Inc.
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14 MeSH Terms
Pyruvate induces torpor in obese mice.
Soto M, Orliaguet L, Reyzer ML, Manier ML, Caprioli RM, Kahn CR
(2018) Proc Natl Acad Sci U S A 115: 810-815
MeSH Terms: Adenosine, Adipose Tissue, Brown, Animals, Brain, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Obese, Obesity, Pyruvic Acid, Torpor, Uncoupling Protein 1
Show Abstract · Added March 22, 2018
Mice subjected to cold or caloric deprivation can reduce body temperature and metabolic rate and enter a state of torpor. Here we show that administration of pyruvate, an energy-rich metabolic intermediate, can induce torpor in mice with diet-induced or genetic obesity. This is associated with marked hypothermia, decreased activity, and decreased metabolic rate. The drop in body temperature correlates with the degree of obesity and is blunted by housing mice at thermoneutrality. Induction of torpor by pyruvate in obese mice relies on adenosine signaling and is accompanied by changes in brain levels of hexose bisphosphate and GABA as detected by mass spectroscopy-based imaging. Pyruvate does not induce torpor in lean mice but results in the activation of brown adipose tissue (BAT) with an increase in the level of uncoupling protein-1 (UCP1). Denervation of BAT in lean mice blocks this increase in UCP1 and allows the pyruvate-induced torpor phenotype. Thus, pyruvate administration induces torpor in obese mice by pathways involving adenosine and GABA signaling and a failure of normal activation of BAT.
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12 MeSH Terms
Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments.
Bolus WR, Peterson KR, Hubler MJ, Kennedy AJ, Gruen ML, Hasty AH
(2018) Mol Metab 8: 86-95
MeSH Terms: Adipose Tissue, Animals, Energy Metabolism, Eosinophils, Insulin, Interleukin-5, Male, Mice, Mice, Inbred C57BL, Obesity
Show Abstract · Added March 14, 2018
OBJECTIVE - Obesity is a metabolic disorder that has reached epidemic proportions worldwide and leads to increased risk for diabetes, cardiovascular disease, asthma, certain cancers, and various other diseases. Obesity and its comorbidities are associated with impaired adipose tissue (AT) function. In the last decade, eosinophils have been identified as regulators of proper AT function. Our study aimed to determine whether normalizing the number of AT eosinophils in obese mice, to those of lean healthy mice, would reduce obesity and/or improve metabolic fitness.
METHODS - C57BL/6J mice fed a high fat diet (HFD) were simultaneously given recombinant interleukin-5 (rIL5) for 8 weeks to increase AT eosinophils. Metabolic fitness was tested by evaluating weight gain, AT inflammation, glucose, lipid, and mixed-meal tolerance, AT insulin signaling, energy substrate utilization, energy expenditure, and white AT beiging capacity.
RESULTS - Eosinophils were increased ∼3-fold in AT of obese HFD-fed mice treated with rIL5, and thus were restored to levels observed in lean healthy mice. However, there were no significant differences in rIL5-treated mice among the above listed comprehensive set of metabolic assays, despite the increased AT eosinophils.
CONCLUSIONS - We have shown that restoring obese AT eosinophils to lean healthy levels is not sufficient to allow for improvement in any of a range of metabolic features otherwise impaired in obesity. Thus, the mechanisms that identified eosinophils as positive regulators of AT function, and therefore systemic health, are more complex than initially understood and will require further study to fully elucidate.
Published by Elsevier GmbH.
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10 MeSH Terms
Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usage, Compared With Blood in HIV-Infected Persons.
Koethe JR, McDonnell W, Kennedy A, Abana CO, Pilkinton M, Setliff I, Georgiev I, Barnett L, Hager CC, Smith R, Kalams SA, Hasty A, Mallal S
(2018) J Acquir Immune Defic Syndr 77: e14-e21
MeSH Terms: Adipose Tissue, Adult, Anti-HIV Agents, Blood Cells, CD8-Positive T-Lymphocytes, Cohort Studies, Female, HIV Infections, Humans, Male, Middle Aged, Receptors, Antigen, T-Cell, Sequence Analysis, DNA, Sustained Virologic Response, T-Lymphocyte Subsets
Show Abstract · Added March 14, 2018
BACKGROUND - Adverse viral and medication effects on adipose tissue contribute to the development of metabolic disease in HIV-infected persons, but T cells also have a central role modulating local inflammation and adipocyte function. We sought to characterize potentially proinflammatory T-cell populations in adipose tissue among persons on long-term antiretroviral therapy and assess whether adipose tissue CD8 T cells represent an expanded, oligoclonal population.
METHODS - We recruited 10 HIV-infected, non-diabetic, overweight or obese adults on efavirenz, tenofovir, and emtricitabine for >4 years with consistent viral suppression. We collected fasting blood and subcutaneous abdominal adipose tissue to measure the percentage of CD4 and CD8 T cells expressing activation, exhaustion, late differentiation/senescence, and memory surface markers. We performed T-cell receptor (TCR) sequencing on sorted CD8 cells. We compared the proportion of each T-cell subset and the TCR repertoire diversity, in blood versus adipose tissue.
RESULTS - Adipose tissue had a higher percentage of CD3CD8 T cells compared with blood (61.0% vs. 51.7%, P < 0.01) and was enriched for both activated CD8HLA-DR T cells (5.5% vs. 0.9%, P < 0.01) and late-differentiated CD8CD57 T cells (37.4% vs. 22.7%, P < 0.01). Adipose tissue CD8 T cells displayed distinct TCRβ V and J gene usage, and the Shannon Entropy index, a measure of overall TCRβ repertoire diversity, was lower compared with blood (4.39 vs. 4.46; P = 0.05).
CONCLUSIONS - Adipose tissue is enriched for activated and late-differentiated CD8 T cells with distinct TCR usage. These cells may contribute to tissue inflammation and impaired adipocyte fitness in HIV-infected persons.
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15 MeSH Terms
Obesity Alters B Cell and Macrophage Populations in Brown Adipose Tissue.
Peterson KR, Flaherty DK, Hasty AH
(2017) Obesity (Silver Spring) 25: 1881-1884
MeSH Terms: Adipose Tissue, Brown, Animals, B-Lymphocytes, Female, Male, Mice, Mice, Inbred C57BL, Obesity
Show Abstract · Added March 14, 2018
OBJECTIVE - The prevalence of obesity continues to rise, and it is understood that regulation of white adipose tissue (WAT) function is important to systemic metabolic homeostasis. Immune cells play a central role in the maintenance of WAT, and their compositions change in number and inflammatory phenotype with the progression of obesity. Because of its energy-burning capabilities, brown adipose tissue (BAT) has become a focus of obesity research. Although novel studies have focused on the function of brown adipocytes in thermogenesis, the tissue as a whole has not been immunologically characterized.
METHODS - BAT immune cell populations were analyzed by flow cytometry and immunohistochemistry in mice with diet-induced obesity (3, 8, or 16 weeks of diet) and in aged mice (1, 6-7, and 10-15 months).
RESULTS - The data confirmed the presence of macrophages and eosinophils, as previously reported, and showed that 20% to 30% of the immune cells in BAT were B cells. The number of B cells and eosinophils increased with diet-induced obesity, whereas macrophages decreased. There was no change in number of any immune cell quantified with age.
CONCLUSIONS - These studies reveal a novel finding of B220 + B cells in BAT and show that BAT immune cell populations change in response to diet-induced obesity.
© 2017 The Obesity Society.
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8 MeSH Terms
Enhancing natriuretic peptide signaling in adipose tissue, but not in muscle, protects against diet-induced obesity and insulin resistance.
Wu W, Shi F, Liu D, Ceddia RP, Gaffin R, Wei W, Fang H, Lewandowski ED, Collins S
(2017) Sci Signal 10:
MeSH Terms: Adipose Tissue, Animals, Dietary Fats, Insulin Resistance, Mice, Mice, Knockout, Obesity, Receptors, Atrial Natriuretic Factor, Signal Transduction
Show Abstract · Added September 25, 2018
In addition to controlling blood pressure, cardiac natriuretic peptides (NPs) can stimulate lipolysis in adipocytes and promote the "browning" of white adipose tissue. NPs may also increase the oxidative capacity of skeletal muscle. To unravel the contribution of NP-stimulated metabolism in adipose tissue compared to that in muscle in vivo, we generated mice with tissue-specific deletion of the NP clearance receptor, NPRC, in adipose tissue ( ) or in skeletal muscle ( ). We showed that, similar to null mice, mice, but not mice, were resistant to obesity induced by a high-fat diet. mice exhibited increased energy expenditure, improved insulin sensitivity, and increased glucose uptake into brown fat. These mice were also protected from diet-induced hepatic steatosis and visceral fat inflammation. These findings support the conclusion that NPRC in adipose tissue is a critical regulator of energy metabolism and suggest that inhibiting this receptor may be an important avenue to explore for combating metabolic disease.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning.
Ferrari A, Longo R, Fiorino E, Silva R, Mitro N, Cermenati G, Gilardi F, Desvergne B, Andolfo A, Magagnotti C, Caruso D, Fabiani E, Hiebert SW, Crestani M
(2017) Nat Commun 8: 93
MeSH Terms: Adipocytes, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Cell Line, Diet, High-Fat, Gene Expression Regulation, Gene Silencing, Histone Deacetylases, Lipid Metabolism, Male, Mice, Mice, Knockout
Show Abstract · Added February 7, 2019
White adipose tissue (WAT) can undergo a phenotypic switch, known as browning, in response to environmental stimuli such as cold. Post-translational modifications of histones have been shown to regulate cellular energy metabolism, but their role in white adipose tissue physiology remains incompletely understood. Here we show that histone deacetylase 3 (HDAC3) regulates WAT metabolism and function. Selective ablation of Hdac3 in fat switches the metabolic signature of WAT by activating a futile cycle of de novo fatty acid synthesis and β-oxidation that potentiates WAT oxidative capacity and ultimately supports browning. Specific ablation of Hdac3 in adipose tissue increases acetylation of enhancers in Pparg and Ucp1 genes, and of putative regulatory regions of the Ppara gene. Our results unveil HDAC3 as a regulator of WAT physiology, which acts as a molecular brake that inhibits fatty acid metabolism and WAT browning.Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning.
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