Thermogenesis is an important component of energy output and therefore a potential target for altering metabolic balance, which in turn can affect obesity-associated disorders such as diabetes. Brown adipose tissue (BAT) is the primary organ for non-shivering thermogenesis and is found both in infants as well as adult humans. Following cold stimulation BAT increases its uptake of long-chain fatty acids (LCFA) from the circulation and channels them toward uncoupled mitochondrial respiration. Thus, both induction/activation of uncoupling protein 1 (UCP1) and LCFA uptake/activation by BAT are essential to thermogenesis. We have shown that Fatty Acid Transport Protein (FATP) 1 is required for the latter process, as FATP1KO mice are severely cold intolerant, have diminished BAT LCFA uptake, and reduced lipid accumulation. Recent findings have indicated that FATP1 may also localize to mitochondria of skeletal muscle and 3T3 L1 adipocytes, however its role, if any in BAT mitochondria is unknown. Further, we found that CD36, a scavenger receptor involved in LCFA uptake, is expressed by BAT and is also required for non-shivering thermogenesis with CD36KO animals displaying severe thermogenic defects. Surprisingly, we found that LCFA uptake by CD36KO BAT was unchanged while fatty acid oxidation was significantly impaired leading to BAT triglyceride accumulation and hypertrophy. A subfraction of CD36 localizes to mitochondria and we are speculating that CD36 may be required for MAT mitochondrial function. Thus, we propose here to test the mechanism by which FATP1 and CD36 support thermogenesis taking into account potential roles in BAT development, lipid metabolism, and mitochondrial function. Results from these studies could lead to novel insights into the regulation of BAT lipid fluxes, mitochondrial function and thermogenesis in this tissue, and ultimately to a better understanding of how energy expenditure is regulated and how it could be utilized for anti-obesity/diabetes strategies.
Obesity, which has several associated diseases including type-2 diabetes, is a result of energy input, i.e. the amount and kinds of food we consume, and our energy output, e.g. exercise and heat production. We have identified two proteins that are required for heat production and propose to study the mechanisms by which they govern energy expenditure.
|Johnson, Amy R; Qin, Yuanyuan; Cozzo, Alyssa J et al. (2016) Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation. Mol Metab 5:506-26|
|Anderson, Courtney M; Kazantzis, Melissa; Wang, Jinshan et al. (2015) Dependence of brown adipose tissue function on CD36-mediated coenzyme Q uptake. Cell Rep 10:505-15|
|Tharp, Kevin M; Jha, Amit K; Kraiczy, Judith et al. (2015) Matrix-Assisted Transplantation of Functional Beige Adipose Tissue. Diabetes 64:3713-24|
|Dubikovskaya, Elena; Chudnovskiy, Rostislav; Karateev, Grigory et al. (2014) Measurement of long-chain fatty acid uptake into adipocytes. Methods Enzymol 538:107-34|
|Godinat, AurÃ©lien; Budin, Ghyslain; Morales, Alma R et al. (2014) A biocompatible "split luciferin" reaction and its application for non-invasive bioluminescent imaging of protease activity in living animals. Curr Protoc Chem Biol 6:169-89|
|Ye, Risheng; Holland, William L; Gordillo, Ruth et al. (2014) Adiponectin is essential for lipid homeostasis and survival under insulin deficiency and promotes Î²-cell regeneration. Elife 3:|
|Anderson, Courtney M; Stahl, Andreas (2013) SLC27 fatty acid transport proteins. Mol Aspects Med 34:516-28|
|Godinat, AurÃ©lien; Park, Hyo Min; Miller, Stephen C et al. (2013) A biocompatible in vivo ligation reaction and its application for noninvasive bioluminescent imaging of protease activity in living mice. ACS Chem Biol 8:987-99|
|Henkin, Amy H; Cohen, Allison S; Dubikovskaya, Elena A et al. (2012) Real-time noninvasive imaging of fatty acid uptake in vivo. ACS Chem Biol 7:1884-91|
|Nie, Biao; Park, Hyo Min; Kazantzis, Melissa et al. (2012) Specific bile acids inhibit hepatic fatty acid uptake in mice. Hepatology 56:1300-10|
Showing the most recent 10 out of 12 publications