Though my prior K08 application was scored favorably, there were some key concerns. In addressing these, I developed a markedly improved proposal. I had aimed to explore how DGAT1 modulates metabolism in the white adipose tissue (WAT), and whether macrophages or adipocytes are dominant in this modulation.
These Aims were based in part on observing that increased expression of the DGAT1 gene (Dgat1) in the adipocyte/macrophage compartment enhanced glucose tolerance in transgenic mice (aP2-Dgat1) on a high-fat diet. I have since expanded these findings, showing that these mice are protected against classical (M1) inflammatory activation and accumulation of macrophages in WAT. Further, Dgat1 expression in macrophages correlated directly with TG storage and inversely with M1 activation by saturated palmitic acid. I thus completed Subaims 2.1, 2.3, and part of 2.2 from the initial proposal, and these data were submitted for publication. This work also prompted the hypothesis that intracellular FAs, in macrophages, adipocytes, or both cell types, regulate inflammatory and metabolic pathways in a DGAT1-sensitive manner. I propose to test this hypothesis in revised Aims with distinct advantages over the prior ones. Finding that DGAT1-deficient (Dgat1-/-) macrophages are vulnerable to M1 activation by palmitate suggests that DGAT1 deficiency in macrophages could be deleterious in vivo. On the other hand, aP2-Dgat1 transgenic mice were protected against the inflammatory and metabolic consequences of DIO, though it is unknown how adipocytes and macrophages contribute to this. I have obtained mouse models to increase or decrease Dgat1 expression specifically in macrophages or adipocytes and will test how each manipulation affects inflammation and metabolism in the revised Aim 1. The revised Aim 2 explores the mechanisms by which intracellular FAs and DGAT1 interact to modulate macrophage activation, and a new Aim 3 focuses on the cross-talk between adipocytes and macrophages. My strategy uses manipulation of Dgat1 mRNA level as a tool to determine how FAs regulate adipocyte and macrophage function. This approach will allow me to enter a new field of study that is entirely distinct from that of my mentor's lab.

Public Health Relevance

Determining how intracellular FAs regulate macrophage activation may yield new clinical targets directly applicable to obesity and diabetes. Identifying which intracellular FAs stimulate macrophage activation is important given the prevalence of high-fat diets. Determining how DGAT1 modulates the response of macrophages and adipocytes to FAs will aid in evaluating the clinical potential of DGAT1 inhibitors in trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08DK080174-03
Application #
8055387
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
3
Fiscal Year
2011
Total Cost
$148,743
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Valdearcos, Martin; Xu, Allison W; Koliwad, Suneil K (2015) Hypothalamic inflammation in the control of metabolic function. Annu Rev Physiol 77:131-60
Valdearcos, Martin; Robblee, Megan M; Benjamin, Daniel I et al. (2014) Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 9:2124-38
Koliwad, Suneil K; Gray, Nora E; Wang, Jen-Chywan (2012) Angiopoietin-like 4 (Angptl4): A glucocorticoid-dependent gatekeeper of fatty acid flux during fasting. Adipocyte 1:182-187
Gray, Nora E; Lam, Lily N; Yang, Karen et al. (2012) Angiopoietin-like 4 (Angptl4) protein is a physiological mediator of intracellular lipolysis in murine adipocytes. J Biol Chem 287:8444-56