Public Health Interests
Aging; Immune functions; Obesity
A major goal of my research program is to obtain creative insights that advance knowledge in the field of Immune-Metabolic interactions that drive adiposity and age-related chronic diseases. Our studies focus on understanding the mechanisms and consequences of aberrant immune-cell activation in adipose tissue microenvironment and age-related ectopic adipocyte development in lymphoid microenvironment like thymus and bone marrow. This Laboratory utilizes basic cellular and molecular tools, genetic manipulations including reporter and Cre/Lox mouse models to understand patho-physiology of obesity and aging. In addition, clinical studies are evaluating the impact of caloric excess and caloric restriction on mechanism that impact inflammation and immune system. The long-term goal of our research is to understand the mechanisms of immune-metabolic crosstalk and to help develop novel approaches to regulate the aberrant immune cell activation as means to enhance healthspan.
Extensive Research Description
The NIH funded projects in the laboratory are –
R01AG043608: (National Institute on Aging)
Inflammasomes and the mechanism of thymic demise in aging.
The Nlrp3 inflammasome senses metabolic ‘danger signals’ and, upon assembly, causes caspase-1 activation, which in turn controls the secretion of pro-inflammatory cytokines IL-1β and IL-18. The central hypothesis of this proposal is that age-related thymic lipotoxicity via a canonical Nlrp3 Inflammasome-dependent mechanism induces ‘sterile thymic inflammation’ and induces T cell dysfunction during aging.
R01AI105097-01: (NIAID) Thymic adipogenesis and age-related thymic demise
With progressive aging, thymus is replaced with ectopic adipocytes and its ability to produce naïve T cells is dramatically diminished. This research project is designed to understand the lineage of adipocytes in aging thymus and to determine the causes and consequences of thymic adiposity and its relationship with immune-senescence.
P01AG051459: (NIA) Impact of FGF21 on healthspan and lifespan.
FGF21 is a unique metabolic hormone as it is secreted in blood from liver in response to starvation and nutrient deprivation to stimulate fatty acid oxidation and to maintain energy balance. Recent studies from our Program Project Team have demonstrated that overexpression of FGF21 in mice extends lifespan, improves insulin-sensitivity and may promote immune function. Based on these data, the central hypothesis of this program project is that FGF21 is a key driver of CNS-adipose tissue-immune system interactions that coordinately promote a pro-longevity molecular program. Overall objective of this project is to elucidate the molecular mechanisms underlying FGF21’s anti-aging effects and to leverage these insights towards inhibiting aging-related chronic diseases
R01AR070811-01. (NIAMS, NIH): Impact of ketones on inflammasome deactivation in Gout
Gout is caused by urate crystal deposition in the joints that cause severe inflammation, pain and joint destruction. There are currently few treatment options for Gouty flares which are episodes of severe pain. The main challenge to manage this disease is the inability to specifically block inflammasome. We have now found that body’s endogenous metabolite, typically produced upon fasting, called ketone body beta-hydroxybutyrate (BHB), can be harnessed to inhibit the inflammasome. The goal of this project to understand the mechanism of action of BHB on myeloid cells and to develop ketone bodies as potential therapeutic against Gout.
- Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Camell CD, Sander J, Spadaro O, Lee A1, Nguyen KY, Wing A, Goldberg EL, Youm YH, Brown CW, Elsworth J, Rodeheffer MS, Schultze JL, Dixit VD (2017). Nature, Oct5 10.1038/nature24022
Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution
Youm YH, Horvath TL, Mangelsdorf DJ, Kliewer SA, Dixit VD. (2016) Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):1026-31
Growth hormone receptor deficiency protects against age-related NLRP3 inflammasome activation and immune-senescence
Spadaro O, Goldberg EL, Camell CD, Youm YH, Kopchick JJ, Nguyem KY, Bartke A, Sun LY and Dixit VD. (2016) Growth hormone receptor deficiency protects against age-related NLRP3 inflammasome activation and immune-senescence. Cell Report, 2016 Feb 11.
The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease
Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD. (2015) The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. Mar;21(3):263-9
Inactivation of C/ebp homologous protein-driven immune-metabolic interactions exacerbate obesity and adipose tissue leukocytosis
Grant R, Nguyen KY, Ravussin A, Albarado D, Youm YH, Dixit VD. (2014) Inactivation of C/ebp homologous protein-driven immune-metabolic interactions exacerbate obesity and adipose tissue leukocytosis. J Biol Chem. May 16;289(20):14045-55.
Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging
Youm YH, Grant RW, McCabe LR, Albarado DC, Nguyen KY, Ravussin A, Pistell P, Newman S, Carter R, Laque A, Münzberg H, Rosen CJ, Ingram DK, Salbaum JM, Dixit VD. (2013) Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. Oct 1;18(4):519-32
The NLRP3 Inflammasome Promotes Age-related Thymic Demise and Immunosenescence
Youm YH, Kanneganti TD, Vandanmagsar B, Zhu X, Ravussin A, Adijiang A, Owen JS, Thomas MJ, Francis J, Parks JS and Dixit VD (2012) The NLRP3 Inflammasome Promotes Age-related Thymic Demise and Immunosenescence. Cell Reports 1, 56-68.
Immunological complications of obesity
Kanneganti TD & Dixit VD. (2012). Immunological complications of obesity. Nat. Immunol. 19;13(8):707-712
The NLRP3 Inflammasome Instigates Obesity-Induced Inflammation and Insulin Resistance
Vandanmagsar B, Youm YH, Ravussin A, Galgani J, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD. (2011) The NLRP3 Inflammasome Instigates Obesity-Induced Inflammation and Insulin Resistance. Nat. Med. 17: 179-188. PMID: 21217695
Thiazolidinedione treatment and constitutive-PPAR? activation induces ectopic adipogenesis and promotes age-related thymic involution
Youm YH, Yang H, Amin R, Smith SR, Leff T, Dixit VD. (2010) Thiazolidinedione treatment and constitutive-PPAR? activation induces ectopic adipogenesis and promotes age-related thymic involution. Aging. Cell Apr 1. Aug;9(4):478-89.PMID: 20374200.
Full List of PubMed Publications
- Lee A, Dixit VD: Energy Sparing Orexigenic Inflammation of Obesity. Cell Metab. 2017 Jul 5. PMID: 28683278
- Spadaro O, Camell CD, Bosurgi L, Nguyen KY, Youm YH, Rothlin CV, Dixit VD: IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge. Cell Rep. 2017 Apr 11. PMID: 28402847
- Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, Morozova-Roche LA, Herzog RI, Iwasaki A, Dixit VD: β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares. Cell Rep. 2017 Feb 28. PMID: 28249154
- Moskalev A, Anisimov V, Aliper A, Artemov A, Asadullah K, Belsky D, Baranova A, de Grey A, Dixit VD, Debonneuil E, Dobrovolskaya E, Fedichev P, Fedintsev A, Fraifeld V, Franceschi C, Freer R, Fülöp T, Feige J, Gems D, Gladyshev V, Gorbunova V, Irincheeva I, Jager S, Jazwinski SM, Kaeberlein M, Kennedy B, Khaltourina D, Kovalchuk I, Kovalchuk O, Kozin S, Kulminski A, Lashmanova E, Lezhnina K, Liu GH, Longo V, Mamoshina P, Maslov A, Pedro de Magalhaes J, Mitchell J, Mitnitski A, Nikolsky Y, Ozerov I, Pasyukova E, Peregudova D, Popov V, Proshkina E, Putin E, Rogaev E, Rogina B, Schastnaya J, Seluanov A, Shaposhnikov M, Simm A, Skulachev V, Skulachev M, Solovev I, Spindler S, Stefanova N, Suh Y, Swick A, Tower J, Gudkov AV, Vijg J, Voronkov A, West M, Wagner W, Yashin A, Zemskaya N, Zhumadilov Z, Zhavoronkov A: A review of the biomedical innovations for healthy longevity. Aging (Albany NY). 2017 Jan 29. PMID: 28132958
- Goldberg EL, Dixit VD: Carnitine acetyltransferase (CRAT) expression in macrophages is dispensable for nutrient stress sensing and inflammation. Mol Metab. 2017 Feb; 2017 Jan 3. PMID: 28180063
- Spadaro O, Goldberg EL, Camell CD, Youm YH, Kopchick JJ, Nguyen KY, Bartke A, Sun LY, Dixit VD: Growth Hormone Receptor Deficiency Protects against Age-Related NLRP3 Inflammasome Activation and Immune Senescence. Cell Rep. 2016 Feb 23; 2016 Feb 11. PMID: 26876170
- Youm YH, Horvath TL, Mangelsdorf DJ, Kliewer SA, Dixit VD: Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc Natl Acad Sci U S A. 2016 Jan 26; 2016 Jan 11. PMID: 26755598
- Camell CD, Nguyen KY, Jurczak MJ, Christian BE, Shulman GI, Shadel GS, Dixit VD: Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity. J Biol Chem. 2015 Dec 4; 2015 Oct 5. PMID: 26438821
- Goldberg EL, Dixit VD: Editorial: "Crowning" eosinophils in adipose tissue: does location matter? J Leukoc Biol. 2015 Oct. PMID: 26429777
- Goldberg EL, Dixit VD: Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev. 2015 May. PMID: 25879284
- Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD: The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015 Mar; 2015 Feb 16. PMID: 25686106
- Grant R, Nguyen KY, Ravussin A, Albarado D, Youm YH, Dixit VD: Inactivation of C/ebp homologous protein-driven immune-metabolic interactions exacerbate obesity and adipose tissue leukocytosis. J Biol Chem. 2014 May 16; 2014 Mar 24. PMID: 24662293
- Nagareddy PR, Kraakman M, Masters SL, Stirzaker RA, Gorman DJ, Grant RW, Dragoljevic D, Hong ES, Abdel-Latif A, Smyth SS, Choi SH, Korner J, Bornfeldt KE, Fisher EA, Dixit VD, Tall AR, Goldberg IJ, Murphy AJ: Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 2014 May 6. PMID: 24807222