The genetic logic of energy metabolism

Cells transform, store, and deploy chemical energy to influence nearly all mammalian physiology. Our research asks how cells make decisions in energy metabolism, how organisms coordinate such decisions to balance energy intake and expenditure, and how new therapies might manipulate these processes to treat disease. The need is pressing: obesity is expected to affect half of American adults by 2030, and many other chronic conditions, such as diabetes and cachexia, also involve dysregulated energy metabolism.

What gives rise to metabolic diseases, and why do these conditions cause so many problems throughout the body—not only cardiovascular, liver, and musculoskeletal dysfunction but even increased risk of infection and of cancer? We believe that investigation of basic gene regulatory mechanisms can help explain the logic behind these complex pathophysiological connections—and provide new avenues for therapy. Toward this goal, we seek genes responsible for the specialized metabolic programs carried out by fat and muscle cells. We then examine the mechanisms by which these genes are activated and carry out their functions, with the hope of discerning the signals that initiate and propagate tissue dysfunction during metabolic disease.

This line of thinking has led us to unexpected roles for mRNA translation in the control of cellular energy metabolism. We identified a translational regulatory element governing cellular respiratory capacity, which we implicated in the evolution of distinct exercise performance phenotypes across species. We also discovered a regulatory axis contributing to diabetes pathogenesis in which obesity causes mitochondrial impairment in fat through translational suppression of specific mRNAs. Other areas of interest include:

•Discovery of mRNA translation programs responsible for cellular metabolic specialization

•Identification of transcription factors that influence cellular fuel choice

•Design of therapies that modulate molecular causes and consequences of obesity-associated inflammation

Our approach demands a coordinated application of genetics, biochemistry, physiology, and bioinformatics to address gene expression mechanisms throughout the central dogma. We therefore recruit talented scientists from a wide array of disciplines, believing that an environment of collaboration and shared curiosity will yield discovery of new biology and opportunity for new therapies.

Georgia O’Keeffe. Black and White, 1930