Diabetes

Group Head: Kei Sakamoto, Ph.D. Contact

Teams:
Chemical Biology: Team Leader: Philipp Gut, M.D. Contact
Circadian Rhythms: Team Leader: Frédéric Gachon, Ph.D. Contact
Metabolic Sensing: Team Leader: Carles Cantó, Ph.D. Contact
Microbiome & Metabolism: Team Leader: Jason Chou, Ph.D. Contact  (INFO WILL FOLLOW)

 

Diabetes

Every human cell in our body is governed by highly complex networks of signaling molecules that work together to maintain metabolic homeostasis. Deregulation of these signaling networks by genetic and/or environmental factors (e.g., lifestyle, nutrition, exercise), as well as aging, plays a fundamental role in developing chronic metabolic diseases, including type 2 diabetes and cardiovascular diseases. Overall aim of our group is to elucidate key molecular and cellular mechanisms that control glucose and energy homeostasis and identify nutritional solutions targeting such mechanisms to maintain metabolic health. One of the key signaling pathways that we focus on is “AMPK (AMP-activated protein kinase)” system, which functions as a central energy sensor and regulator of energy balance at both cellular and whole-body levels.

Key Goals

  • Underpin key molecular signaling network/mechanism by which nutrients, exercise, and hormones controls carbohydrate and lipid metabolism at peripheral (e.g. muscle and liver) and whole-body levels.
  • Explore and validate natural products aimed at maintaining and improving Metabolic Health.

 

Key Publications of the Group*

Ducommun S, Deak M, Sumpton D, Ford RJ, Núñez Galindo A, Kussmann M, Viollet B, Steinberg GR, Foretz M, Dayon L, Morrice NA, Sakamoto K. Motif affinity and mass spectrometry proteomic approach for the discovery of cellular AMPK targets: identification of mitochondrial fission factor as a new AMPK substrate. Cell Signal, 27, 978-88, 2015.

Patel K, Foretz M, Marion A, Campbell DG, Gourlay R, Boudaba N, Tournier E, Titchenell P, Peggie M, Deak M, Wan M, Kaestner KH, Göransson O, Viollet B, Gray NS, Birnbaum MJ, Sutherland C, Sakamoto K. The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver. Nature Commun, 5, 4535, 2014.

Hunter RW, Foretz M, Bultot L, Fullerton MD, Deak M, Ross FA, Hawley SA, Shpiro N, Viollet B, Barron D, Kemp BE, Steinberg GR, Hardie DG, Sakamoto K. Mechanism of action of compound-13: an α1-selective small molecule activator of AMPK. Chem Biol, 21,866-79, 2014. See news release

Zeqiraj E, Tang X, Hunter RW, García-Rocha M, Judd A, Deak M, von Wilamowitz-Moellendorff A, Kurinov I, Guinovart JJ, Tyers M*, Sakamoto K*, Sicheri F*. Structural basis for the recruitment of glycogen synthase by glycogenin. Proc Natl Acad Sci U S A, E2831-40, 2014. (*equal contribution).

Hawley, S. A., Fullerton, M. D., Ross, F. A., Schertzer, J. D., Chevtzoff, C., Walker, K. J., Peggie, M. W., Zibrova, D., Green, K. A., Mustard, K. J., Kemp, B. E., Sakamoto, K., Steinberg, G. R. and Hardie, D. G. The ancient drug salicylate directly activates AMP-activated protein kinase. Science, 336, 918-922, 2012.

Chen, S., Wasserman, D.H., MacKintosh, C., Sakamoto, K. Mice with AS160/TBC1D4-Thr649Ala knockin mutation are glucose intolerant with reduced insulin sensitivity and altered GLUT4 trafficking. Cell Metab, 13, 68-79, 2011.

 

 

Chemical Biology

Team Leader: Philipp Gut, M.D. Contact

Cumulating damage to mitochondria during aging leads to reduced bioenergetics, metabolic inflexibility and ultimately loss of tissue function. Our team aims to identify natural bioactives that enhance mitochondrial function and restore metabolic homeostasis in pathologies that are caused or driven by mitochondrial dysfunction. A main focus is to leverage these bioactives for the development of therapies for aging-related muscle disease and diabetes.

Key Goals

  • Perform natural bioactive screening for molecules that improve mitochondrial metabolic flexibility.
  • Identify bioactives or nutritional interventions that improve the cellular quality control and turnover of mitochondria.
  • Probe the efficacy of these compounds on the outcome of pathological conditions related to mitochondrial dysfunction.

 

Key Publications of the Group*

Gut, P., Reischauer, S., Arnaout, R., Stainier, D.Y.R. Little fish, big data: the zebrafish as a model for cardiovascular and metabolic disease (2017). Physiological Reviews 97(3):889-938.

Gut, P. and Verdin, E. (2013). The nexus of chromatin regulation and intermediary metabolism. Nature 502(7472):489-498.

Rardin, M.J., He W., Nishida, Y., Newman, J.C., Carrico, C., Danielson, S.R., Guo, A., Gut, P., Sahu, A.K., Li, B., Uppala, R., Fitch, M, Riiff, T., Lei, Z., Zhou, J., Mulhern, D., Stevens, R.D., Ilkayeva, O.R., Newgard, C.B., Jacobson, M.P., Hellerstein, M., Goetzman, E.S., Gibson, B.W. and Verdin, E. (2013). SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metabolism 18(6):920-933.

Gut, P., Baeza-Raja, B., Andersson, O., Hasenkamp, L., Hsiao, J., Hesselson, D., Akassoglou, K., Verdin, E., Hirschey, M.D. and Stainier, D.Y.R. (2012). Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism. Nature Chemical Biology 9:97-104.

Andersson, O., Adams, B.A., Yoo, D., Ellis, G.C., Gut, P., Anderson, R.M., German, M.S. and Stainier, D.Y.R. (2012). Adenosine signaling promotes regeneration of pancreatic beta cells in vivo. Cell Metabolism 15(6):885-94.

 

 

Circadian Rhythms

Team Leader: Frédéric Gachon, Ph.D. Contact

The goal of the Circadian Rhythms group is to understand the link between metabolism, feeding rhythms, and the circadian clock, in order to clarify how biological rhythm manipulations, through feeding schedule, could be used to improve mammalian physiology.

Key Goals

  • Provide better characterization of the molecular mechanism of the mammalian circadian clock.
  • Deliver mechanism involved in the establishment of the final outcome of the circadian clock: rhythmic protein expression and activity.
  • Develop functional interconnection between mammalian physiology and the circadian clock.
  • Determine how rhythmic protein secretion is orchestrated by rhythmic feeding and its impact on physiology.

 

Key Publications of the Group*

Wang J.,Mauvoisin D., Martin E., Atger F., Núñez Galindo A., Dayon L., Sizzano F., Palini A., Kussmann M., Waridel P., Quadroni M., Dulić V., Naef F., and Gachon F. Nuclear proteomics uncovers diurnal regulatory landscapes in mouse liver, Cell Metab., 2017.

Jouffe C., Gobet C., Martin E., Métairon S., Morin-Rivron D., Masoodi M., and Gachon F. Perturbed rhythmic activation of signaling pathways in mice deficient for Sterol Carrier Protein 2-dependent diurnal lipid transport and metabolism, Sci Rep., 2016.

Atger F., Gobet C., Marquis J., Martin E., Weger B., Lefebvre G., Descombes P., Naef F., and Gachon F. Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver, Proc Natl Acad Sci U S A, 2015.

Mauvoisin D., Wang J., Jouffe C., Martin E., Atger F., Waridel P., Quadroni M., Gachon F., and Naef F.  Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver, Proc Natl Acad Sci. USA, 2014.

Dallmann R., Brown S. A., and Gachon F. Chronopharmacology: New Insights and Therapeutic Implications, Annu Rev Pharmacol Toxicol., 2014.

Jouffe C., Cretenet G., Symul L., Martin E., Atger F., Naef F., and Gachon F.  The circadian clock coordinates ribosome biogenesis, PLoS Biol, e1001455, 2013.

 

 

Metabolic Sensing

Team Leader: Carles Cantó, Ph.D. Contact

The overall mission of our group is to understand how regulatory enzyme activities can sense nutritional and energetic cues and use this information to promote metabolic adaptations and grant metabolic flexibility. We particularly focus on sensing mechanisms affected in complex metabolic diseases, such as type 2 diabetes and obesity.

Key Goals

  • Understand how enzymatic sensors transfer their information.
  • Evaluate how mitochondrial dynamics influence metabolic adaptation.
  • Understand the transcriptional modulation of metabolic flexibility.
  • Understanding the role of NAD+ metabolism in health and disease.

 

Key Publications of the Group*

Greggio C, Jha P, Kulkarni SS, Lagarrigue S, Broskey NT, Boutant M, Wang X, Conde Alonso S, Ofori E, Auwerx J, Cantó C, Amati F. Enhanced Respiratory Chain Supercomplex Formation in Response to Exercise in Human Skeletal Muscle. Cell Metab. 2017 Feb 7;25(2):301-311.

Kulkarni SS, Joffraud M, Boutant M, Ratajczak J, Gao AW, Maclachlan C, Hernandez-Alvarez MI, Raymond F, Metairon S, Descombes P, Houtkooper RH, Zorzano A, Cantó C. Mfn1 Deficiency in the Liver Protects Against Diet-Induced Insulin Resistance and Enhances the Hypoglycemic Effect of Metformin. Diabetes. 2016 Dec;65(12):3552-3560.

Ratajczak J, Joffraud M, Trammell SA, Ras R, Canela N, Boutant M, Kulkarni SS, Rodrigues M, Redpath P, Migaud ME, Auwerx J, Yanes O, Brenner C, Cantó C. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun. 2016 Oct 11;7:13103.

Boutant M, Kulkarni SS, Joffraud M, Raymond F, Métairon S, Descombes P, Cantó C. SIRT1 Gain of Function Does Not Mimic or Enhance the Adaptations to Intermittent Fasting, Cell Reports, 14, 1–8, March 8, 2016.

Boutant M, Joffraud M, Kulkarni SS, Garcia-Casarrubios E,  Garcia-Roves PM, Ratajczak J, Fernandez-Marcos PJ, Valverde AM, Serrano M, Cantó C. SIRT1 enhances glucose tolerance by potentiating brown adipose tissue function, Molecular Metabolism, 4(2), 118-131, 2015.

Boutant M, Kulkarni SS, Joffraud M, Ratajczak J, Valera-Alberni M, Combe R, Zorzano A, Cantó C. Mfn2 is critical for brown adipose tissue thermogenic function. EMBO J. 2017 Jun 1; 36(11):1543-1558.

 

 

Microbiome & Metabolism

Team Leader: Jason Chou, Ph.D. Contact  (INFO WILL FOLLOW)



*Some of these publications were done before the scientist/s joined the Nestlé Institute of Health Sciences