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Marc R. Montminy

 

Marc R. Montminy

Marc R. Montminy

Professor
J.W. Kieckhefer Foundation Fund
Clayton Foundation Laboratories for Peptide Biology

"Obesity is a major risk factor in the development of adult-onset diabetes, which is characterized by the inability of cells in the body to respond to insulin. By studying key genetic switches that control food intake and metabolism, we hope to identify molecules that will be amenable to drug therapy for insulin-resistant individuals."

Obesity, which is probably the most important factor in the development of insulin resistance–promotes insulin resistance through the inappropriate inactivation of a process called gluconeogenesis, where the liver creates glucose for fuel and which ordinarily occurs only in times of fasting. Yet, not all obese people become insulin resistant, and insulin resistance occurs in non-obese individuals, leading Montminy and his team to suspect that fasting-induced glucose production was only half the story.

It had been known that a condition known as ER (endoplasmatic reticulum) stress is abnormally active in livers of obese individuals, where it contributes to the development of hyperglycemia, or high blood glucose levels. Glucose production is turned on by a transcriptional switch called CRTC2, which normally sits outside the nucleus waiting for the signal that allows it to slip inside and do its work. Once in the nucleus, it teams up with a protein called CREB, and together they switch on the genes necessary to increase glucose output. In insulinresistant mice, however, the CRTC2 switch seems to get stuck in the "on" position, and the cells start churning out glucose like sugar factories in overdrive.

Surprisingly, when the researchers mimicked the conditions of ER stress in lean mice, CRTC2 moved to the nucleus but failed to activate gluconeogenesis. Instead, it switched on genes important for combating stress and returning cells to health. On closer inspection, they found that in this scenario CRTC2 did not bind to CREB but instead joined forces with another factor, called ATF6a. What's more, like jealous lovers CREB and ATF6a are competing for CRTC2's affection–the more ATF6a is bound to CRTC2, the less there is for CREB to bind to. This clever mechanism ensures that a cell in survival mode automatically shuts down glucose production, thus saving energy. Under the kind of persistent stress presented by obesity, however, levels of ATF6a go down, triggering aberrant glucose production in the liver, and explaining how obesity sets the stage for diabetes and why thin people can become insulin-resistant.

Lab Photo

Left to right:
Standing: Sam Van de Velde, Jose Paz, Kim Ravnskjaer, Biao Wang, Youngsup Song, Jeong Ho Kim, Marc Montminy, Bing Luan, Hongbo Wang, Pankaj Singh, Naomi Goebel, Nina Miller, Jason Goode, Noel Moya

Seated: Motoyuki Igata, Yi Liu, Yiguo Wang, Liliana Vera, Susie Hedrick, Kristin Viste, Meghan Hogan

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Marc R. Montminy

Faculty

Marc R. Montminy

Marc R. Montminy

Professor
J.W. Kieckhefer Foundation Fund
Clayton Foundation Laboratories for Peptide Biology

Marc Montminy is a professor in the Clayton Foundation Laboratories for Peptide Biology. Montminy's lab isolated cDNA clones for the cAMP response element binding protein (CREB) in 1989. cAMP was found to regulate cellular genes via the PKA mediated phosphorylation of CREB at SER133. This modification was shown to promote target gene activation via the recruitment of the coactivator CBP. Structural studies of the CREB/CBP complex revealed that CREB phosphorylation promotes recruitment of CBP via allosteric and direct mechanisms. The structure also suggested the potential for developing small molecules that block target gene activation by disrupting the CREB: CBP complex.

Current work in the lab focuses on the identification of CREB target genes and characterization of agonists and antagonists that may be used to evaluate the importance of CREB in mediating cellular responses to various stimuli. Montminy also conducts research on the genetic basis of diabetes. Using knockout and transgenic approaches, the Montminy laboratory determined that CREB performs a critical role in glucose homeostasis during fasting. They found that CREB triggers the gluconeogenic program via induction of the nuclear hormone receptor coactivator PGC-1a. Following up on these studies, Montminy identified a second family of cAMP regulated CREB coactivators, called TORCs, which are critical for induction of gluconeogenic genes during fasting. They showed that TORC2 activity is inhibited by AMPK-mediated phosphorylation, providing an important link between energy-sensing and hormonal pathways. Indeed, oral hypoglycemic agents such as metformin, which activate AMPK, were found to reduce hepatic glucose production by inhibiting TORC2 activity. Future work using mice with knockouts in TORC family members will reveal the extent to which these coactivators promote energy balance in other insulin-sensitive tissues.

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