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Marc R. Montminy

 

Marc R. Montminy

Marc R. Montminy

Professor
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."

Through years of research, Montminy and his team have uncovered a family of genes that act as metabolic switches, turning other genes on or off. One gene, TORC2, functions as a "fasting" switch, flipping on the production of glucose in the liver when blood glucose levels run low, usually during sleep. During the day, the hormone insulin normally shuts down TORC2, ensuring that blood sugar levels don't rise too high. Problems along the pathway, however, can help lead to diabetes. In their latest study, Montminy and his group looked at the function of TORC1, which unlike TORC2 and TORC3 is produced in the brain but whose function was unknown.

Mice genetically engineered to lack both copies of the TORC1 gene looked fine at birth, but at about eight weeks, they began to gain weight and became persistently obese in adulthood; they also became insulin resistant. Surprisingly, mice of both sexes were also infertile. Body weight and fertility have long been known to be related to each other. Women who are too thin, for example, can have trouble becoming pregnant.

From an evolutionary point of view, that makes perfect sense: If a woman lacks sufficient body fat reserves, a fetus's growth in the womb could be stunted.

It turns out that TORC1, which is found within nerve cells, responds to signals from leptin, a powerful hormone that travels through the bloodstream to the brain, reporting how much fat is in storage. Acting as a master switch, TORC1 then turns on a spate of genes, two of which are well-known. One is the CART gene, which is known to stifle appetite. The other, KISS1 (named by its discoverers at the Penn State Hershey Medical Center), is required for reproduction; mutations in the gene produce human infertility. When mice inherited only one TORC1 gene (instead of the normal two, one from each parent), fertility was restored but the mice gained more weight than normal mice.

These findings suggest that variations in the TORC1 gene could contribute a genetic component to obesity and infertility and might be regulated with a novel drug.

Lab Photo

Left to right:
Back row: Yiguo Wang, Jose Paz, Jason Goode, Sam Van de Velde, Motoyuki Igata, Susie Hedrick, Youngsup Song, Biao Wang, Kim Ravnskjaer, Jeong Ho Kim, Pankaj Singh Front row: Liliana Vera, Rebecca Berdeaux, Nina Miller, Marc Montminy, Naomi Goebel, Judith Altarejos, Yi Liu, Noel Moya

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Marc R. Montminy

Faculty

Marc R. Montminy

Marc R. Montminy

Professor
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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