It has been proposed that dysregulation of the fuel sensing enzyme AMPK is a pathogenic factor for type 2 diabetes and other disorders linked to the metabolic syndrome and a target for their therapy. Other studies have suggested a similar role for the sirtuin SIRT1, an NAD-dependent histone/protein deacetylases, best known as a possible mediator of the increased longevity caused by caloric restriction. In the preceding grant period, we discovered that SIRT1 can activate AMPK by deacetylating its upstream kinase LKB1 and two other groups found that AMPK can activate SIRT1, suggesting the existence of a SIRT1/AMPK cycle. The applicability of these findings to models other than a few cell lines and their physiological and clinical relevance remain to be established. Upon this background, studies will be carried out in cultured cells, rodents and humans with the following four specific aims: (1) To examine the workings of the AMPK/SIRT1 signaling mechanism in cultured adipocytes and pancreatic ?-cells (which produce insulin). (2) To determine whether AMPK/SIRT1 signaling interacts with a recently defined glycerolipid/free fatty acid cycle to maintain the integrity and function of adipocytes and ?-cells. (3) To assess how the two cycles interact with each other in vivo during exercise, starvation/refeeding and diet- induced obesity. (4) To determine if the AMPK/SIRT1 mechanism is depressed in adipose tissue of massively obese humans with insulin resistance. This is a particularly interesting group since we have already found that AMPK activity is diminished in these individuals, compared to comparably obese individuals who are insulin sensitive, and that this is associated with a large increase in the expression of inflammatory markers.

Public Health Relevance

Two integral features of type 2 diabetes in many individuals are a progressive loss of function of insulin- producing pancreatic ?-cells which produce insulin and resistance of peripheral tissues to insulin. This project will explore the interaction of an AMPK/SIRT1 cycle and a glycerolipid/free fatty acid cycle. We will expand on preliminary data that suggest joint dysregulation of the two cycles contributes to the oxidative stress, inflammation and other changes that lead both to insulin resistance and impaired insulin secretion in the setting of diabetes. If successful the end result could be the identification of new therapeutic targets for diabetes prevention and therapy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Laughlin, Maren R
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Boston Medical Center
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Xu, X Julia; Valentine, Rudy J; Ruderman, Neil B (2014) AMP-activated Protein Kinase (AMPK): Does This Master Regulator of Cellular Energy State Distinguish Insulin Sensitive from Insulin Resistant Obesity? Curr Obes Rep 3:248-55
Valentine, Rudy J; Coughlan, Kimberly A; Ruderman, Neil B et al. (2014) Insulin inhibits AMPK activity and phosphorylates AMPK Ser???/??ยน through Akt in hepatocytes, myotubes and incubated rat skeletal muscle. Arch Biochem Biophys 562:62-9
Lamontagne, Julien; Jalbert-Arsenault, Elise; Pepin, Emilie et al. (2013) Pioglitazone acutely reduces energy metabolism and insulin secretion in rats. Diabetes 62:2122-9
Xu, X Julia; Pories, Walter J; Dohm, Lynis G et al. (2013) What distinguishes adipose tissue of severely obese humans who are insulin sensitive and resistant? Curr Opin Lipidol 24:49-56
Ruderman, Neil B; Carling, David; Prentki, Marc et al. (2013) AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 123:2764-72
Ido, Yasuo; Duranton, Albert; Lan, Fan et al. (2012) Acute activation of AMP-activated protein kinase prevents H2O2-induced premature senescence in primary human keratinocytes. PLoS One 7:e35092
Xu, X Julia; Gauthier, Marie-Soleil; Hess, Donald T et al. (2012) Insulin sensitive and resistant obesity in humans: AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue. J Lipid Res 53:792-801
Nelson, Lauren E; Valentine, Rudy J; Cacicedo, Jose M et al. (2012) A novel inverse relationship between metformin-triggered AMPK-SIRT1 signaling and p53 protein abundance in high glucose-exposed HepG2 cells. Am J Physiol Cell Physiol 303:C4-C13
Saha, Asish K; Xu, X Julia; Balon, Thomas W et al. (2011) Insulin resistance due to nutrient excess: is it a consequence of AMPK downregulation? Cell Cycle 10:3447-51
Gauthier, Marie-Soleil; O'Brien, Elena L; Bigornia, Sherman et al. (2011) Decreased AMP-activated protein kinase activity is associated with increased inflammation in visceral adipose tissue and with whole-body insulin resistance in morbidly obese humans. Biochem Biophys Res Commun 404:382-7

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