Activation of lipolysis can alternatively promote lipotoxicity or enhance oxidative lipid disposal by improving mitochondrial function. Precisely how and why lipolysis can have these divergent effects remains a mystery. This knowledge gap represents an important problem given the numerous diseases (i.e. obesity, diabetes) and therapies (i.e. insulin) that influence lipolysis. The long-term goal of this research program is t determine how lipolysis alternatively contributes to metabolic benefit versus harm. The overall objective of this proposal is to characterize the impact of adipocyte lipolysis on adipose tissue function itself. The central hypothesis is that adipocyte lipolysis generates essential lipid signas required to maintain, and even promote, metabolic homeostasis within adipose tissue. Disruption in the release of these lipid signals impairs adipose tissue function, whereas enhanced release of these lipid signals improves adipose tissue function. We further hypothesize that PPAR? is a critical mediator of these effects. This hypothesis is based on 1) the phenotypes of humans lacking key lipolytic proteins, 2) our data demonstrating that chronic impairment of adipocyte lipolysis reduces PPAR? target gene expression and promotes adipose tissue dysfunction and lipodystrophy, and 3) evidence suggesting that lipolysis generates essential lipid signals (i.e. for PPARs). The rationale for the proposed research is that characterization of the biological variables and underlying mechanisms by which lipolysis (and specific lipases) alternatively promote or prevent adipose tissue dysfunction will lead to new approaches for preventing or treating metabolic disease. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) to determine the physiological relevance and natural history of adipose tissue phenotypes resulting from long-term changes in adipocyte lipolysis as well as the role of PPAR activation in mediating these effects; and 2) to determine the impact of key biological variables influencing lipolysis-induced FA signaling on adipocyte phenotype, mitochondrial function, and PPAR activation.
In Aim 1, we will use established methods to characterize the adipose tissue phenotype of young versus old mice with adipocyte-specific increases or decreases in key lipases (adipose triglyceride lipase and hormone-sensitive lipase).
In Aim 2, we will use both cell and animals models to determine how key biological variables (i.e. magnitude/duration/type of stimulus, enzyme releasing FA s, source and type FAs) influence mitochondrial function and PPAR signaling in adipocytes. This approach is innovative, in the applicant's opinion, because it departs from the status quo (increasing lipolysis is bad, decreasing lipolysis is good) by shifting focus onto the beneficial effect of lipolysis (increasing lipolysis is good, decreasing lipolysis is bad). The proposed research is significant because it is expected to have broad translation importance in the prevention and treatment of a wide range of metabolic diseases. Ultimately, such knowledge is expected to improve our understanding of numerous diseases and therapies that impact lipolysis as well as provide new targets for prevention and/or therapeutic intervention.

Public Health Relevance

The proposed research is relevant to public health because adipocyte lipolysis and adipose tissue function are essential for metabolic homeostasis. This is relevant to the NIH mission of improving the understanding, prevention, and/or treatment of metabolic diseases such as diabetes, obesity, and cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56DK090166-06
Application #
9211580
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Teff, Karen L
Project Start
2011-02-01
Project End
2017-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kim, Soohyun P; Li, Zhu; Zoch, Meredith L et al. (2017) Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner. JCI Insight 2:
Scerbo, Diego; Son, Ni-Huiping; Sirwi, Alaa et al. (2017) Kidney triglyceride accumulation in the fasted mouse is dependent upon serum free fatty acids. J Lipid Res 58:1132-1142
Heckmann, Bradlee L; Zhang, Xiaodong; Saarinen, Alicia M et al. (2017) Liver X receptor?mediates hepatic triglyceride accumulation through upregulation of G0/G1 Switch Gene 2 expression. JCI Insight 2:e88735
Mottillo, Emilio P; Balasubramanian, Priya; Lee, Yun-Hee et al. (2014) Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic ?3-adrenergic receptor activation. J Lipid Res 55:2276-86