Lipid homeostasis in adipose tissue is a critical determinant of whole body metabolism. When the efficiency with which adipocytes store or release triglycerides is perturbed, lipids accumulate in non-adipocytes, impairing systemic metabolism and altering the function of key tissues, including liver, heart, skeletal muscle and pancreas. Despite our understanding of canonical pathways that regulate lipolysis and lipogenesis in adipocytes, the factors that contribute to lipid homeostasis in adipose tissue are incompletely defined. In our efforts to understand non- inflammatory function of immune cells in adipose tissue, we have recently discovered that in addition to canonical release of lipids via neutral lipases, adipocytes release lipid in triglyceride-rich exosomes which are taken up by adipose tissue macrophages (ATMs) and catabolized in lysosomes. Studies supported by this grant originally identified immune cells, and in particular macrophages, as important components of adipose tissue that respond to and contribute to adipocyte function. Since these original observations most studies have focused on the inflammatory roles of immune cells and how they can impair insulin signaling, and thereby perturb systemic lipid and carbohydrate metabolism. We have hypothesized that ATMs have adaptive functions necessary for normal adipose tissue metabolism and indeed, others have shown that ATMs participate in adipose tissue differentiation, thermogenesis and vascularization. During the current funding cycle we found that obesity increases not only the number of ATMs but their uptake and lysosomal-dependent catabolism of neutral lipid. As we investigated the source of ATM lipid, we found not unexpectedly nearly all the lipid is adipocyte derived. However, surprisingly lipid accumulation in ATMs does not require the canonical lipolytic pathway mediated by neutral lipases. Instead, adipocytes release triglyceride-rich exosomes that both provide lipid to and induce differentiation of ATMs. This establishes exosomes as components of adipose tissue lipid metabolism and regulators of immune function. Based on our preliminary data and previous clinical and murine studies, we propose that adipocyte-derived exosomes and ATMs are necessary components in a lipid cycle required for normal adipose tissue maintenance and function. The work proposed in this application will characterize these exosomes, how they affect ATM recruitment and differentiation, and whether local lysosomal hydrolysis of lipid by ATMs is required to prevent lipoatrophy.

Public Health Relevance

? Obesity is defined by the expansion of adipose tissue and is a leading cause of type 2 diabetes, non-alcoholic fatty liver disease and dyslipidemia. Understanding how adipose tissue macrophages contribute to adipose tissue health and dysfunction will identify therapeutic strategies to combat obesity-associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK066525-16
Application #
9694202
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2003-09-15
Project End
2022-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
16
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Ravussin, Yann; Edwin, Ethan; Gallop, Molly et al. (2018) Evidence for a Non-leptin System that Defends against Weight Gain in Overfeeding. Cell Metab 28:289-299.e5
Diamond, Joshua M; Arcasoy, Selim; McDonnough, Jamiela A et al. (2017) Adipose Gene Expression Profile Changes With Lung Allograft Reperfusion. Am J Transplant 17:239-245
Chang, Hye Rim; Kim, Hae Jin; Xu, Xiaoyuan et al. (2016) Macrophage and adipocyte IGF1 maintain adipose tissue homeostasis during metabolic stresses. Obesity (Silver Spring) 24:172-83
Grijalva, Ambar; Xu, Xiaoyuan; Ferrante Jr, Anthony W (2016) Autophagy Is Dispensable for Macrophage-Mediated Lipid Homeostasis in Adipose Tissue. Diabetes 65:967-80
Edwin, Ethan A; Ferrante Jr, Anthony W (2015) Keeping Off the Weight with DCs. Immunity 43:624-6
Subramanian, Manikandan; Ozcan, Lale; Ghorpade, Devram Sampat et al. (2015) Suppression of Adaptive Immune Cell Activation Does Not Alter Innate Immune Adipose Inflammation or Insulin Resistance in Obesity. PLoS One 10:e0135842
Ravussin, Yann (2015) Temperature matters with rodent metabolic studies. Obesity (Silver Spring) 23:1330
Ericksen, Russell E; Rose, Shannon; Westphalen, Christoph Benedikt et al. (2014) Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response. Gut 63:385-94
Kim-Muller, Ja Young; Zhao, Shangang; Srivastava, Shekhar et al. (2014) Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice. Cell Metab 20:593-602
Ravussin, Yann; Leibel, Rudolph L; Ferrante Jr, Anthony W (2014) A missing link in body weight homeostasis: the catabolic signal of the overfed state. Cell Metab 20:565-72

Showing the most recent 10 out of 26 publications