Mailing Address 660 S. Euclid Ave.
Campus Box 8127
St. Louis, MO 63110
Office Phone (314) 362-3688
Lab Phone 314-362-2541
Obesity enhances macrophage recruitment into and the inflammatory state of adipose tissue, promoting insulin resistance. However, focusing on macrophage inflammatory signaling is simplistic and limits understanding of disease pathogenesis. Recent phenotyping of adipose tissue macrophages upon dietinduced obesity demonstrates induction of autophagy-lysosomal biogenesis and lysosomal lipolysis, suggesting that macrophage recruitment to lipid-overloaded adipose tissues might also be compensatory in nature. Indeed, overexpression of macrophage TFEB, a master transcriptional regulator of this response, ameliorates diet-induced obesity and glucose intolerance. Can macrophage autophagy-lysosomal biogenesis be leveraged therapeutically to treat obesity and insulin resistance? We have discovered a sugar called trehalose that appears to have the unique ability to activate macropahge TFEB with potential metabolic benefits. In Aim 1, this trehalose-TFEB-metabolism link will be explored. However, a major impediment to the therapeutic use of trehalose is mammalian trehalase, which readily degrades it to glucose. In Aim 2, genetic and pharmacological means of trehalase inhibition will be used to determine if trehalose’s metabolic benefits can be synergized. This proposal will test the hypothesis that harnessing autophagylysosomal biogenesis in macrophages is a viable strategy to treat obesity and diabetes.