Anutosh Chakraborty, Ph.D.

Associate Professor
Pharmacology and Physiology

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Education

Ph.D. Indian Institute of Chemical Biology, Jadavpur, India 2005
"Chaperonic Function of a Cyclophilin Homolog from Leishmania donovani"

M.Sc. Burdwan University, India 1997
Zoology (First class)

B.Sc. Burdwan University, India 1995
Zoology major, Chemistry, Botany (First Class)

Previous Positions

Associate Professor
St. Louis University School of Medicine, St. Louis, MO. Aug 2017-

Associate Professor
Scripps Research Institute, Jupiter, Florida. June 2017-July 2017

Assistant Professor
The Scripps Research Institute, Jupiter, Florida. 2012-June 2017

Research Associate and Instructor
Johns Hopkins Medical School, Baltimore, Maryland 2008-2012

Postdoctoral fellow
Johns Hopkins Medical School, Baltimore, Maryland 2005-2008

Research Trainee
Johns Hopkins Medical School, Baltimore, Maryland 2004-2005

Research

A complete knowledge of functions of all the cellular protein components is essential to understand various aspects of cell biology. Employing diverse approaches, our laboratory attempts to unravel impacts of novel proteins on cell metabolism and survival. The ultimate goal is to discover hitherto unknown targets in diseases. A major focus of the laboratory is to determine in vivo significance of the mammalian inositol hexakisphosphate kinases (IP6Ks), which generate the inositol pyrophosphate 5-IP7. Genetic and pharmacologic studies conducted in the laboratory reveal influences of this pathway in various diseases such as, obesity, type-2 diabetes (T2D), hepatosteatosis and osteoporosis.

Obesity, a global epidemic, is a major factor driving the explosion of type-2 diabetes (T2D). In the US, 34.9% adults are obese, of which 9.3% also have T2D. Obesity/T2D leads to various other life-threatening diseases such as heart diseases, stroke and neurodegeneration. Although lifestyle interventions are effective for obesity/T2D management, a significant number of patients exhibit inadequate long-term responses. Thus, pharmacotherapy is essential to treat or prevent obesity. Unfortunately, current anti-obesity medications are only partly effective, due to substantial side effects, inability to maintain weight loss over a prolonged period and non-responsiveness to a considerable number of patients. Therefore, new drugs with anti-obesity and anti-diabetic effects are urgently needed. Our laboratory performs extensive research to understand the biology of obesity/T2D. We discovered that inositol hexakisphosphate kinase-1 (IP6K1) is a novel target in obesity/T2D.

PUBLISHED RESEARCH

IP6K1, the major murine IP6K isoform, promotes insulin resistance in high fat diet (HFD)-fed mice. Moreover, IP6K1 reduces energy expenditure. As a result, global IP6K1 knockout (IP6K1-KO) mice are protected from diet induced obesity (DIO) and insulin resistance (Chakraborty et al. Cell, 2010). IP6K1 promotes weight gain and insulin resistance by diminishing energy expenditure and insulin signaling in the adipose tissue. Consequently, adipocyte-specific IP6K1-KO (AdKO) mice are also resistant to DIO (Figure 1). Moreover, the pan IP6K inhibitor TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates DIO and insulin resistance (Figure 2). IP6K1 regulates diverse pathways such as Akt and AMPK in the adipocytes to influence insulin signaling and energy metabolism (Figure 3) (Zhu et al. JCI, 2016, Zhu et al. Mol. Metab. 2016; Ghoshal et al. Mol. Metab. 2016).



ONGOING RESEARCH

Determine tissue-specific roles of IP6K1: Studies using the global knockout mouse models reveal functions of IP6K1 in various tissues such as adipose tissue, muscle, liver, brain and testis, of which only adipose tissue specific functions of IP6K1 is validated using a tissue-specific knockout mouse model. Current research is focused on understanding functions of IP6K1 in other tissues.

Development of isoform-selective IP6K inhibitors: Although the pan IP6K inhibitor TNP has anti-obesity and anti-diabetic potential, it has several shortcomings, which must be addressed prior to its advancement to the next level. Therefore, several collaborative approaches are being taken to develop potent and specific IP6K1 inhibitors, which will significantly advance inositol pyrophosphate and energy metabolism research. These compounds may also emerge as anti-obesity/anti-T2D drugs.

Decipher impacts of IP6K1 regulation in vivo: LC-MS/MS studies identified several ubiquitinated and phosphorylated residues in IP6K1. Research is ongoing to determine impacts of these posttranslational modifications on IP6K1 mediated cellular processes.

Investigate in vivo significance of hitherto uncharacterized proteins in cell metabolism and survival: Published genome wide association, transcriptomic and proteomic studies by various laboratories together with our ongoing studies, identified that a number of proteins are altered in various diseases, although their roles and regulations are unknown. The long-term goal of the laboratory is to elucidate functions of these proteins, with a hope that one/few would emerge as novel therapeutic targets.

Publications

Chakraborty A. The inositol pyrophosphate pathway in health and diseases. Biol Rev Camb Philos Soc. (2017), doi: 10.1111/brv.12392 (Review).

Boregowda SV, Ghoshal S, Booker CN, Krishnappa V, Chakraborty A and Phinney DG*. IP6K1 Reduces Mesenchymal Stem/Stromal Cell Fitness and Potentiates High Fat Diet-Induced Skeletal Involution. Stem Cells. 2017, 35, 1973-1983.

Zhu Q, Ghoshal S, Tyagi R and Chakraborty A*. Global IP6K1 deletion enhances temperature modulated energy expenditure which reduces carbohydrate and fat induced weight gain. Mol. Metab., (2016), 6, 73-85.

Zhu Q, Ghoshal S, Rodrigues A, Gao S, Asteian A, Kamenecka TM, Barrow JC and Chakraborty A*. Adipocyte-specific IP6K1 deletion reduces diet-induced obesity by enhancing AMPK mediated thermogenesis. J. Clin. Invest., (2016), 126, 4273-4288.

Ghoshal S, Zhu Q, Asteian A, Lin H, Xu H, Ernst G, Barrow JC, Xu B, Cameron MD, Kamenecka TM and Chakraborty A*. TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates diet induced obesity and insulin resistance via inhibition of the IP6K1 pathway. Mol. Metab., (2016), 5, 903-17.

Ghoshal S, Tyagi R, Zhu Q and Chakraborty A*. Inositol hexakisphosphate kinase-1 interacts with perilipin1 to modulate lipolysis. Int J Biochem Cell Biol., (2016), 78, 149-155.

Rao F, Xu J, Khan AB, Gadalla MM, Cha JY, Xu R, Tyagi R, Dang Y, Chakraborty A and Snyder SH. Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4-Signalosome complex to regulate DNA repair and cell death. Proc. Natl. Acad. Sci. USA., (2014), 111, 16005-10.

Chakraborty A*, Latapy C*, Xu J, Snyder SH and Beaulieu JM. Inositol hexakisphosphate-1 regulates behavioral response in mice via Akt/GSK3 regulation. Mol. Psychiatry, (2014), 19, 284-293. *Equal contribution.

Prasad A*, Jia Y*, Chakraborty A, Li Y, Jain SK, Zhong J, Roy SG, Loison F, Mondal S, Sakai J, Blanchard C, Snyder SH, Luo HR. Inositol hexakisphosphate kinase 1 (InsP6K1) is a key modulator of neutrophil function in innate immunity via negative regulation of PtdIns(3,4,5)P3 signaling. Nat. Immunol., (2011), 12, 752-60.

Kim S, Kim SF, Maag D, Maxwell MJ, Resnick AC, Juluri KR, Chakraborty A, Koldobskiy MA, Cha SH, Barrow R, Snowman AM, Snyder SH. Amino Acid Signaling to mTOR Mediated by Inositol Polyphosphate Multikinase. Cell Metab. (2011), 13, 215-221.

Chakraborty A*, Werner JK Jr*, Koldobskiy MA, Mustafa AK, Juluri KR, Pietropaoli J, Snowman AM and Snyder SH. Caesin Kinase-2 mediates cell survival through phosphorylation and degradation of Inositol hexakisphosphate kinase-2. Proc. Natl. Acad. Sci. USA., (2011), 108, 2205-2209. *Equal contribution.

Chakraborty A, Kim S and Snyder SH. Inositol Pyrophosphates as Mammalian Cell Signals. Sci. Signal. (2011), 4, re1 (Review).

Chakraborty A, Koldobskiy MA, Bello NT, Maxwell M, Potter JJ, Juluri KR, Maag D, Kim S, Huang AS, Dailey MJ, Saleh M, Snowman AM, Moran TH, Mezey E and Snyder SH. Inositol pyrophosphates inhibit Akt signaling, regulate insulin sensitivity and weight gain. Cell., (2010), 143, 897-910.

Koldobskiy MA, Chakraborty A, Snowman AM, Juluri KR, Vandiver MS, Heletz S and Snyder SH. p53 mediated apoptosis requires Inositol Hexakisphosphate Kinase-2. Proc. Natl. Acad. Sci. USA., (2010), 107, 20947-20951.

Mustafa AK, van Rossum DB, Patterson RL, Maag D, Ehmsen JT, Gazi SK, Chakraborty A, Barrow RK, Amzel LM and Snyder SH. Serine Racemase Regulation by Glutamate Transmission via Reversal of PIP2 Inhibition. Proc. Natl. Acad. Sci. USA., (2009), 106, 2921-6.

Chakraborty A, Koldobskiy MA, Sixt KM, Juluri K, Mustafa AK, Snowman AM, van Rossum DB, Patterson RL, and Snyder SH. From the cover: HSP90 Regulates Cell Survival via Inositol Hexakisphosphate Kinase-2. Proc. Natl. Acad. Sci. USA., (2008), 105, 1134-9.

Bhandari R, Chakraborty A and Snyder SH. Inositol pyrophosphate pyrotechnics. Cell Metab. (2007), 5, 321-3 (Preview).

Sen B, Venugopal V, Chakraborty A, Datta R, Dolai S, Banerjee R, Datta AK. Amino acid residues of Leishmania donovani cyclophilin key to interaction with its adenosine kinase: biological implications. Biochemistry., (2007), 46, 7832-43.

Sen B, Chakraborty A, Datta R, Bhattacharyya B and Datta A. K. Reversal of ADP-mediated aggregation of adenosine kinase by cyclophilin lead to its reactivation. Biochemistry., (2006), 45, 263-71.

Datta R, Das I, Sen B, Chakraborty A, Adak S, Mandal C and Datta AK. Homology model guided site-specific mutagenesis reveals the mechanisms of substrate binding and product-regulation of adenosine kinase from Leishmania donovani. Biochem. J., (2006), 394, 35-42.

Datta R, Das I, Sen B, Chakraborty A, Adak S, Mandal C, and Datta AK. Mutational Analysis of Active Site Residues Crucial for the Catalytic Activity of Adenosine Kinase from Leishmania donovani. Biochem J., (2005), 387, 591-600.

Chakraborty A, Datta R, Sen B, and Datta AK. Isomerase-independent chaperone-function of Cyclophilin ensures aggregation prevention of Adenosine Kinase both in vitro and under in vivo conditions. Biochemistry., (2004), 43, 11862-72.

Chakraborty A, Das I, Datta R, Sen B, Bhattacharyya D, Mandal C, and Datta AK. A single-domain cyclophilin from Leishmania donovani reactivates soluble aggregates of Adenosine Kinase in an isomerase-independent chaperone function. J. Biol. Chem., (2002), 277, 47451-47460.

Grants

R01 DK103746-01 
04/11/15 – 03/31/20
Source: NIH/NIDDK
"Inositol hexakisphosphate kinase-1 As a Novel Target in Obesity"
To determine how IP6K1 mediated regulation of adipose tissue metabolism modulates energy homeostasis in obesity and diabetes.
Role: Principal Investigator

Honors and Awards

Ranked 2nd at the All India Graduate Aptitude Test in Engineering (GATE) 1999

Awarded 'Lectureship' after qualifying the CSIR/UGC Test (NET) 1998

Awarded 'Research Fellowship' after qualifying the CSIR/UGC Test (NET) 1999

Professional Organizations and Associations

The Obesity Society

American Diabetic Association