Faculty & Research
|School of Medicine Address||725 N. Wolfe Street|
Baltimore MD 21205
Research Topic: Regulatory pathways that control adaptive metabolic responses in adipose and skeletal muscle tissues.
Organisms go through cycles of metabolic activity, driven by internal cues (circadian, circannual clocks) and physiologic/behavioral inputs (e.g. feeding/fasting, physical activity/rest). In addition, organisms face environmental challenges (physical, chemical or psychological stressors) that require continual adaptation of the pathways regulating metabolism. The goal of our research is to elucidate the regulatory and transcriptional mechanisms that integrate information and enable physiologic adaptations (particularly in response to changes in physical activity, environmental temperature, nutritional state), and that, when deregulated, contribute to metabolic disease.
Our studies focus on the Estrogen-Related Receptors (ERRα, ERRβ, and ERRγ), which we use as an entry point to the study of the regulatory / transcriptional networks that are important for adaptation in adipose tissue and in skeletal muscle, in response to changes in environmental temperature, physical exercise and/or diet. In past studies, we have shown that ERRs, and in particular ERRα, co-ordinate gene expression programs that regulate mitochondrial biogenesis and oxidative capacity. Our current studies build on this past work, using mouse models with genetically modified loci for ERRs (floxed alleles) and dissecting the unique and shared roles of ERRs in adipose tissue and in skeletal muscle. We are also identifying novel mechanisms that regulate ERR activity, as well as new important downstream effectors of ERRs, thereby expanding the network of regulators of mitochondrial oxidative function. Our studies identify and probe new avenues for therapeutic intervention in states where oxidative metabolism and tissue function are compromised, such as insulin resistance and type 2 diabetes, disease-associated muscle atrophies and age-related degenerative diseases.
Complementary roles of Estrogen-Related Receptors in brown adipocyte thermogenic function. Gantner ML, Hazen BC, Eury E, Brown EL, Kralli A.
Endocrinology. 2016 Oct 20:en20161767. PMID: 27763777
Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle. Cho Y, Hazen BC, Gandra PG, Ward SR, Schenk S, Russell AP, Kralli A. FASEB J. 2016 Feb;30(2):674-87. doi: 10.1096/fj.15-276360. PMID: 26481306
PGC-1α and PGC-1β increase CrT expression and creatine uptake in myotubes via ERRα. Brown EL, Snow RJ, Wright CR, Cho Y, Wallace MA, Kralli A, Russell AP.
Biochim Biophys Acta. 2014 Dec;1843(12):2937-43. doi: 10.1016/j.bbamcr.2014.08.010. PMID: 25173818 Free Article
GADD45γ regulates the thermogenic capacity of brown adipose tissue. Gantner ML, Hazen BC, Conkright J, Kralli A. Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11870-5. doi: 10.1073/pnas.1406638111. PMID: 25071184 Free PMC Article
Mice lacking PGC-1β in adipose tissues reveal a dissociation between mitochondrial dysfunction and insulin resistance. Enguix N, Pardo R, González A, López VM, Simó R, Kralli A, Villena JA. Mol Metab. 2013 Jun 5;2(3):215-26. doi: 10.1016/j.molmet.2013.05.004. PMID: 24049736 Free PMC Article
PGC-1β and ChREBP partner to cooperatively regulate hepatic lipogenesis in a glucose concentration-dependent manner. Chambers KT, Chen Z, Lai L, Leone TC, Towle HC, Kralli A, Crawford PA, Finck BN. Mol Metab. 2013 May 9;2(3):194-204. doi: 10.1016/j.molmet.2013.05.001. PMID: 24049734 Free PMC Article
Ndrg2 is a PGC-1α/ERRα target gene that controls protein synthesis and expression of contractile-type genes in C2C12 myotubes. Foletta VC, Brown EL, Cho Y, Snow RJ, Kralli A, Russell AP. Biochim Biophys Acta. 2013 Dec;1833(12):3112-23. doi: 10.1016/j.bbamcr.2013.08.011. PMID: 24008097 Free Article
Peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1)- and estrogen-related receptor (ERR)-induced regulator in muscle 1 (Perm1) is a tissue-specific regulator of oxidative capacity in skeletal muscle cells. Cho Y, Hazen BC, Russell AP, Kralli A. J Biol Chem. 2013 Aug 30;288(35):25207-18. doi: 10.1074/jbc.M113.489674. PMID: 23836911 Free PMC Article
Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism.
Gan Z, Rumsey J, Hazen BC, Lai L, Leone TC, Vega RB, Xie H, Conley KE, Auwerx J, Smith SR, Olson EN, Kralli A, Kelly DP. J Clin Invest. 2013 Jun;123(6):2564-75. doi: 10.1172/JCI67652. PMID: 23676496 Free PMC Article
Disruption of skeletal muscle mitochondrial network genes and miRNAs in amyotrophic lateral sclerosis. Russell AP, Wada S, Vergani L, Hock MB, Lamon S, Léger B, Ushida T, Cartoni R, Wadley GD, Hespel P, Kralli A, Soraru G, Angelini C, Akimoto T. Neurobiol Dis. 2013 Jan;49:107-17. doi: 10.1016/j.nbd.2012.08.015.