Borcherding N, Jia W, Giwa R, Field RL, Moley JR, Kopckey BJ, Chan MM, Yang BQ, Sabio JM, Walker EC, Osorio O, Bredemeyer A, Pietka T, Alexander-Brett J, Morley SC, Artyomov MN, Abumrad NA, Schilling J, Lavine K, Crewe C, Brestoff JR. (2022) Dietary Lipids Inhibit Mitochondria Transfer to Macrophages to Divert Adipocyte-derived Mitochondria to Blood for Distribution to Distant Organs. Cell Metabolism. Aug 30:S1550-4131(22)00353-9. doi: 10.1016/j.cmet.2022.08.010. Epub ahead of print. PMID: 36070756.
Crewe C, Chen S, Bu D, Gliniak CM, Asterholm IW, Yu XX, Joffin N, de Souza CO, Funcke JB, Oh DY, Varlamov O, Robino JJ, Gordillo R, Scherer PE. (2022) Deficient Caveolin-1 Synthesis in Adipocytes Stimulates Systemic Insulin-independent Glucose Uptake via Extracellular Vesicles. Diabetes. db220035. https://doi.org/10.2337/db22-0035
Crewe C, Funcke JB, Li S, Joffin N, Gliniak CM, Ghaben AL, An YA, Sadek HA, Gordillo R, Akgul Y, Chen S, Samovski D, Fischer-Posocszky P, Kusminski CM, Klein S and Scherer PE. (2021) Extracellular vesicle-based Interorgan Transport of Mitochondria from Energetically Stressed Adipocytes. Cell Metabolism. 33(9): 1853-1868 e1811.
In this publication, we demonstrated that adipocytes undergoing mitochondria-specific energetic stress, as in the obese condition, release small EVs (sEVs) containing mitochondrial particles that are respiration-competent but oxidatively damaged. These EV-enclosed mitochondria enter circulation and are taken up by cardiomyocytes. There they elicit transient mitochondrial dysfunction of the host network and free radical production. This is not a pathological process but, instead, results in robust adaptation of the heart to combat this adipocyte sEV-imposed stress.
Zhu Y, Li N, Huang M, Bartels M, Dogné S, Zhao S, Chen X, Crewe C, Straub L, Vishvanath L, Zhang Z, Shao M, Yang Y, Gliniak CM, Gordillo R, Smith GI, Holland WL, Gupta RK, Dong B, Caron N, Xu Y, Akgul Y, Klein S, Scherer PE. 2021 Adipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL-316,243-stimulated lipolysis. Nature Communications. 12(1):4829. doi: 10.1038/s41467-021-25025-4.
Zhang Z, Funcke JB, Zi Z, Zhao S, Straub LG, Zhu Y, Zhu Q, Crewe C, An YA, Chen S, Li N, Wang MY, Ghaben AL, Lee C, Gautron L, Engelking LJ, Raj P, Deng Y, Gordillo R, Kusminski CM, Scherer PE. 2021 Adipocyte iron levels impinge on a fat-gut crosstalk to regulate intestinal lipid absorption and mediate protection from obesity. Cell Metabolism. 33(8):1624-1639.e9. doi: 10.1016/j.cmet.2021.06.001.
Joffin N, Paschoal VA, Gliniak CM, Crewe C, Elnwasany A, Szweda LI, Zhang Q, Hepler C, Kusminski CM, Gordillo R, Oh DY, Gupta RK, Scherer PE. (2021) Mitochondrial metabolism as a key regulator of the fibro-inflammatory and adipogenic stromal subpopulations in white adipose tissue. Cell Stem Cell. 28(4):702-717.e8.doi: 10.1016/j.stem.2021.01.002.
Kusminski CM, Ghaben AL, Morley TS, Samms RJ, Adams AC, An Y, Johnson JA, Joffin N, Onodera T, Crewe C, Holland WL, Gordillo R, Scherer PE. (2019). A Novel Model of Diabetic Complications: Adipocyte Mitochondrial Dysfunction Triggers Massive β-Cell Hyperplasia. Diabetes. db190327.
An YA, Crewe C, Asterholm IW, Sun K, Chen D, Zhang F, Shao M, Funcke JB, Zhang Z, Straub L, Yoshino J, Klein S, Kusminski CM, Scherer PE. (2019) Dysregulation of Amyloid Precursor Protein Impairs Adipose Tissue Mitochondrial Function and Promotes Obesity. Nature Metabolism. 1, 1243–1257 doi:10.1038/s42255-019-0149-1
Zhang Z, Shao M, Hepler C, Zi Z, Zhao S, An YA, Zhu Y, Ghaben A, Wang MY, Li N, Onodera T, Joffin N, Crewe C, Zhu Q, Vishvanath L, Kumar A, Xing C, Wang QA, Gautron L, Deng Y, Gordillo R, Kruglikov I, Kusminski CM, Gupta RK, Scherer PE. (2019). Dermal Adipose Tissue has High Plasticity and Undergoes Reversible Dedifferentiation in Mice. JCI. 10.1172/JCI130239
Crewe C., Zhu Y., Paschoal VA., Joffin N., Ghaben AL., Gordillo R., Oh DY, Liang G., Horton JD., and Scherer PE. (2019). SREBP-regulated Adipocyte Lipogenesis is Dependent on Substrate Availability and Redox Modulation of mTORC1. JCI Insight. 10.1172/jci.insight.129397
Bu D., Crewe C., Kusminski CM., Gordillo R., Ghaben AL., Kim M., Park J., Deng H., Xiong W., Liu XZ., Lonning PE., Halberg N., Rios A., Chang Y., Gonzalez A., Zhang N., An Z., Scherer PE. (2019). Human Endotrophin as a Driver of Malignant Tumor Growth. JCI Insight. 10.1172/jci.insight.125094
Crewe C., Joffin N., Rutkowski J.M., Kim M., Zhang F., Towler D.A., Gordillo R., Scherer P.E. (2018). An Endothelial to Adipocyte Extracellular Vesicle Axis Governed by Metabolic State. Cell. 175(3):695-708.e13.
We have uncovered the existence of extracellular vesicle (EV)-mediated signaling between cell types within the adipose tissue (AT) proper. This phenomenon became evident in our attempts at generating an adipocyte-specific knock out of caveolin 1 (cav1) protein. While we effectively ablated the CAV1 gene in adipocytes, cav1 protein remained abundant. With the use of newly generated mouse models, we show that neighboring endothelial cells (ECs) transfer cav1-containing EVs to adipocytes in vivo, which reciprocate by releasing EVs to ECs. AT-derived EVs contain proteins and lipids capable of modulating cellular signaling pathways. Furthermore, this mechanism facilitates transfer of plasma constituents from ECs to the adipocyte. The transfer event is physiologically regulated by fasting/refeeding and obesity, suggesting EVs participate in the tissue response to changes in the systemic nutrient state. This work offers new insights into the complex signaling mechanisms that exist between adipocytes, stromal vascular cells and potentially distal organs
Crewe C., Schafer C., Lee I., Kinter M., Szweda LI. (2017) Regulation of pyruvate dehydrogenase kinase 4 in the heart through degradation by the Lon protease in response to mitochondrial substrate availability. J. Biol. Chem. 292 (1), 305-312
Asterholm I.W., Kim J., Rutkowski J.M., Tao C., Crewe C., and Scherer PE. (2016). Pathological Type-2 Immune Response, Enhanced Tumor Growth, and Glucose Intolerance in Retnlβ (RELMβ) Null Mice: A Model of Intestinal Immune System Dysfunction in Disease Susceptibility. American Journal of Pathology. 186(9) 2404-16.
Crewe, C., Kinter, M., and Szweda, L. I. (2013) Rapid Inhibition of Pyruvate Dehydrogenase: An Initiating Event in High Dietary Fat-Induced Loss of Metabolic Flexibility in the Heart. PLoS ONE 8, e77280