Metabolism and Diabetes Platform — Team Science Grants

Title: Link between insulin resistance and myelinogenesis in the central nervous system

Investigative team: Isobel A. Scarisbrick, Ph.D., Aleksey Matveyenko, Ph.D., Ian R. Lanza, Ph.D., Nathan K. LeBrasseur, M.S., Ph.D.

Central hypothesis: The focus of the insulin resistance and myelinogenesis grant is to uncover how systemic metabolic dysfunction affects the function of neural cells in the brain and spinal cord and whether insulin-sensitizing strategies already in clinical practice can be applied to improve nervous system function and repair.

Metabolic syndrome affects one-quarter of the world's population and is a leading cause of cardiovascular disease and type 2 diabetes. Systemic metabolic dysfunction has also emerged as a risk factor for cognitive decline in Alzheimer's disease, and recent findings suggest its impact on nervous system function is far wider-ranging, including myelin-producing cells across the brain and spinal cord.

The investigative team is testing the hypothesis that the negative impact of systemic metabolic dysfunction on the nervous system is mediated in part by the same insulin resistance that affects organ function elsewhere in the body. In this case, neural cells are no longer able to take up enough glucose (energy) to meet their high demands and therefore become dysfunctional, show limited regeneration and become vulnerable to degeneration.

Potential outcomes and advances: The investigative team expects that findings will shed new light on mechanisms of sensory and motor functional decline in people with metabolic syndrome. The findings may suggest new therapeutic opportunities for neuroprotection and for facilitating the brain's capacity for reparative regeneration and rehabilitation.

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Title: Investigating mitochondrial complex I inhibitors as novel therapeutics for mitochondrial genetic diseases of the electron transport chain

Investigative team: Stephen C. Ekker, Ph.D., Eugenia Trushina, Ph.D., Devin Oglesbee, Ph.D.

Central hypothesis: This project tests a fundamental question in metabolism: Does increasing mitochondrial energetics reverse key molecular, cellular and organismal markers of distinct classes of mitochondrial disease?

Mitochondria are the body's key cellular energy source and play a critical role in health. However, defective mitochondrial function is associated with a diversity of diseases, and there is no cure for mitochondria-specific diseases. It is generally accepted that breakdowns of bioenergetics play major roles in mitochondrial diseases, so identifying new methods for increasing bioenergetics is critical.

The investigative team has identified potential new drugs that increase cellular bioenergetics, CP2 and C458. In preliminary work, these candidate drugs counterintuitively work by insulting energy production, which results in a net increase in mitochondrial resistance to stress and augmented bioenergetic reserve. In this grant, the team is studying CP2 and C458 in the specific context of mitochondrial disease models that affect the machinery responsible for energy production.

The investigative team uses both human cell lines in vitro and zebrafish in vivo as complementary model systems to triangulate cell-specific and tissue-specific results to identify areas of overlap that are likely to represent valuable insight for potential use in patients. In combination, these tools will help pinpoint whether the team's novel class of drugs can reverse the effects of poor energy production in mitochondria.

Potential outcomes and advances: Any signatures of mitochondrial disease identified through this study will represent hypothesis-generating signals for understanding how intervening in mitochondrial energetics impacts cellular and animal models. The resulting new class of compounds will represent potential leads for direct clinical testing in patients.

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Title: How can white adipose tissue be converted to energy-consuming brown fat?

Investigative team: Jun Liu, M.D., Ph.D., Lawrence J. Mandarino, Ph.D., Wayne T. Willis, Paul R. Langlais, Ph.D.

Central hypothesis: The imbalance between energy intake and expenditure can lead to obesity and metabolic disorders such as type 2 diabetes. White adipocytes store triglycerides in large, single-lipid droplets and release fatty acids for consumption by other tissues. Brown adipocytes, characterized by many small lipid droplets, metabolize fatty acids to generate heat. Beige (brite) adipocytes behave like brown adipocytes, but appear in white adipose tissue with long-term cold exposure.

The investigators hypothesize that brite and white adipocytes represent two interconvertible states and that expression of the novel protein FSP27 critically mediates changes in adipocyte identity.

Potential outcomes and advances: Understanding the basic mechanisms underlying the use of fuels to generate heat, as opposed to storing them as fat, could lead to pharmaceutical interventions to increase nonexercise energy expenditure in people with obesity, making it easier for them to lose weight and lower disease burden.

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Title: Basic mechanisms of fat toxicity in the liver

Investigative team: Yi Guo, Ph.D., Gregory J. Gores, M.D., Harmeet Malhi, MBBS, Taofic Mounajjed, M.D., Jan van Deursen, Ph.D.

Central hypothesis: Nonalcoholic fatty liver disease (NAFLD) is a complex disorder with limited therapeutic options for patients with progressive disease. Saturated free fatty acids induce hepatocyte toxicity, a pivotal process in NAFLD progression, by evoking a network of poorly understood adverse signaling events. The goals of this collaborative study are to identify novel mediators and pathways responsible for hepatocyte lipotoxicity in NAFLD.

Potential outcomes and advances: Understanding the molecular mechanism of lipotoxicity will lead to strategies designed to protect the liver against fat-induced damage and provide new therapeutic targets to prevent disease progression in NAFLD. The widespread occurrence of this life-threatening condition compels a more complete understanding of the basic mechanisms of this disorder.

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Title: Metabolic interventions in polycystic kidney disease

Investigative team: Eduardo N. Chini, M.D., Ph.D., Vicente E. Torres, M.D., Ph.D., Peter C. Harris, Ph.D., Cheryl A. Conover, Ph.D.

Central hypothesis: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases, affecting more than 12.5 million people worldwide. ADPKD is characterized by an accumulation of kidney cysts that ultimately leads to kidney failure. Its present treatment is largely supportive, and no specific or effective treatment options are available.

Mounting evidence points to the central role of cellular energy metabolism in the pathogenesis of ADPKD. In particular, the evidence suggests that nutritional manipulation through caloric restriction may be a novel therapeutic approach for ADPKD. The investigators hypothesize that caloric restriction regulates metabolism in ADPKD, and that it can provide clues to the molecular mechanisms and signaling pathways that promote metabolic adaptations and cyst formation in ADPKD.

Potential outcomes and advances: Understanding the mechanisms that lead to ADPKD is imperative for the development of effective therapeutic options for this serious disorder.

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