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.
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
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.
Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in the age-related thymic involution
Yang H, Youm YH, and Dixit VD. (2009). Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in the age-related thymic involution. J. Immunol. 183(5):3040-52. PMCID: PMC2731487
Obesity Accelerates Thymic Aging
Yang H, Youm YH, Vandanmagsar B, Rood J, Kumar KG, Butler AA and Dixit VD. (2009) Obesity Accelerates Thymic Aging. Blood. 114(18):3803-3812. PMID: 19648267