- PhD, University of California, San Francisco
Molecular mechanisms linking inflammation and insulin signaling to control cell growth and metabolism
The obesity rate in the United States has soared over the past few decades, and so too has the prevalence of type 2 diabetes, which now affects nearly 30 million Americans. The burden of diabetes is felt not only in terms of physical suffering and mortality, but also in terms of the economic toll of the disease, which amounted to $245 billion in 2012. The strongest risk factor for type 2 diabetes is obesity, yet how increased fat mass leads to diabetes is a fundamental, unanswered question. Considerable genetic evidence suggests that interactions between adipocytes and macrophages that infiltrate adipose tissue in the obese state lead to insulin resistance first in fat and then in liver and muscle. However, the mechanism(s) that lead to decreased insulin signal transduction in response to inflammatory signaling and that result in whole-body insulin resistance are poorly understood.
In animals as diverse as fruit flies and humans, insulin-like hormones activate a highly conserved signal transduction pathway leading to phosphorylation of the kinase Akt and subsequent activation of growth and nutrient metabolism via phosphorylation of target proteins. In Drosophila, the insulin signaling pathway acts in the fat body to promote nutrient storage and growth of the whole animal. This organ also directs the humoral arm of the innate immune response. We have shown that the interaction between the innate immune and insulin signaling pathways observed in mammals is conserved in Drosophila. Activating innate immune signaling by infection or by transgenic expression of an activated Toll receptor in the Drosophila fat body impairs Akt activation and leads to decreased growth of the whole animal.
Our lab uses forward genetics in Drosophila melanogaster to identify genes that rescue insulin resistance and growth inhibition due to activated innate immune signaling in the fat body. Such genes may mediate interactions between the Toll and insulin signaling pathways, or they may encode molecules that permit the fat body to communicate a growth signal to the rest of the fly. We use mosaic analysis to test whether rescuing genes act cell autonomously to regulate insulin signaling and analyses of whole-animal growth and nutrient storage to assess global insulin sensitivity. We are also interested in the metabolic effects of innate immune signaling in the fat body, as activation of Toll signaling leads to altered expression of genes encoding enzymes of fatty acid and sphingolipid metabolism, enzymes required for purine synthesis and a large number of nutrient transporters.
Ultimately, we hope to identify new regulators of insulin signaling as well as signals that mediate communication between organs both during normal growth and in the development of whole-body insulin resistance. Our studies focus on genes with clear human orthologues in order to identify novel genes that have relevance to human disease. Furthermore, as our approach is unbiased, it has great potential for discovery of new targets for the treatment of diabetes.
- Measurement of Carbon Dioxide Production from Radiolabeled Substrates in Drosophila melanogaster. Journal of visualized experiments : JoVE. 2016;. PMID: 27404635
- Bland M, Birnbaum M. Cell biology. ADaPting to energetic stress. Science (New York, N.Y.). 2011;332(6036): 1387-8. PMID: 21680830
- Bland M, Lee R, Magallanes J, Foskett J, Birnbaum M. AMPK supports growth in Drosophila by regulating muscle activity and nutrient uptake in the gut. Developmental biology. 2010;344(1): 293-303. PMID: 20478298 | PMCID: PMC2909368
- DiAngelo J, Bland M, Bambina S, Cherry S, Birnbaum M. The immune response attenuates growth and nutrient storage in Drosophila by reducing insulin signaling. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(49): 20853-8. PMID: 19861550 | PMCID: PMC2791644
- Bland M, Fowkes R, Ingraham H. Differential requirement for steroidogenic factor-1 gene dosage in adrenal development versus endocrine function. Molecular endocrinology (Baltimore, Md.). 2004;18(4): 941-52. PMID: 14726490
- Bland M, Desclozeaux M, Ingraham H. Tissue growth and remodeling of the embryonic and adult adrenal gland. Annals of the New York Academy of Sciences. 2003;995 59-72. PMID: 12814939
- Bland M, Jamieson C, Akana S, Dallman M, Ingraham H. Gene dosage effects of steroidogenic factor 1 (SF-1) in adrenal development and the stress. Endocrine research. 2001;26(4): 515-6. PMID: 11196422
- Bland M, Jamieson C, Akana S, Bornstein S, Eisenhofer G, Dallman M, Ingraham H. Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(26): 14488-93. PMID: 11121051 | PMCID: PMC18946