Differentiation and Function of Adipocytes and Energy Metabolism

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One of the most fundamental questions in biology is how cells commit to specific lineages and regulate their terminal differentiation programs and how this process is related to their function in whole body physiology and disease. To understand this process, we use adipogenesis as a model system and study the molecules that control differentiation and function in these cells. We have discovered that the GATA family of transcription factors play a critical role in adipocyte differentiation during the transition from preadipocytes to adipocytes. The molecular mechanisms underlying their biology are currently being studied using molecular and cellular approaches. We are also developing tissue-specific gain- and loss-of-function mouse models to study regulation of adipocyte precursors and GATA factors and co-factors. Through this line of research we hope to generate further insights into the process of adipocyte differentiation and the integration of positive and negative hormonal and metabolic signals that regulate the program of differentiation. This information could prove useful in the development of new tools for prevention and treatment of obesity.

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Fig. 1. The adipocyte in three perspectives: focus on the endoplasmic reticulum (ER). Adipocyte morphology in three perspectives illustrating its organization.
A: Scanning electron micrograph of mouse adipose tissue, courtesy of Tae-Hwa Chun and Stephen Weiss (88).
B: Hematoxylin and eosin-stained section of mouse adipose tissue, courtesy of Drs. Steven Shoelson and Ali Nayer.
C: Electron micrograph of 3T3-L1 adipocyte ER surrounding a lipid droplet (LC, lipid core; SL, surface layer), reproduced with permission (Blanchette -Mackie et al 21.)
D: Adipocyte ER functions include protein translation, triglyceride (TG) droplet synthesis, and cholesterol and nutrient sensing.
Artistic design by Deniz Hotamisligil.

Adipocytes have specific needs and confront enormous challenges during their life cycle.  Not only do they process and store molar quantities of lipids, face severe architectural constraints to accommodate cytoplasm and organelles, and mobilize lipids when needed, but they also maintain and regulate a very active repertoire of secreted products of both protein and lipid nature, and withstand the stresses associated with their physiological function under circumstances of additional burden such as exposure to excess nutrients.  During differentiation, these cells undergo a massive and remarkable transformation, introducing all of these properties into a fibroblast-like cell.  Hence, adipocyte differentiation requires active stress management and adaptation of organelle capacity to the synthetic, secretory and other demands of the cell.  We are currently exploring the regulation and involvement of endoplasmic reticulum responses during this process and how the function of this organelle is coupled to differentiation and proper function of adipocytes. Most recently, we discovered an unexpected role for adipocytes and adipocyte UPR pathways in supporting lactational metabolism. Adaptations to lactation involve one of the most profound transformations of adipose tissue, and this process is critical for the success of breast feeding, a fundamental requirement for mammalian survival. Hence, we are interested in exploring this unique biology and underlying mechanisms further.

Finally, we are exploring the role of UPR regulation and metaflammation in the two main branches of adipocytes and adipose tissue, white and brown, with distinct and unique biology. Among others, white adipose tissue is principally involved in energy and nutrient storage whereas brown adipose tissue is a site for massive energy and substrate expenditure. We are currently exploring the adaptive systems these cells employ to accommodate their specialized needs and unique physiological properties of the tissues in which they reside.

Suggested reading from our lab:

Gregor MF, Misch ES, Yang L, Hummasti S, Inouye KE, Lee AH, Bierie B, Hotamisligil GS. The Role of Adipocyte XBP1 in Metabolic Regulation during Lactation. Cell Reports, 2013 May 30;3(5):1430-9. Abstract | PDF

Gregor MF, Hotamisligil GS. Adipocyte Stress: The endoplasmic reticulum and metabolic disease. J of Lipid Research 2007, 48(9): 1905-144. Abstract | PDF

Wellen K, Fucho R, Gregor MF, Furuhashi M, Morgan C, Lindstad T, Vaillancourt E, Gorgun CZ, Saatcioglu F, Hotamisligil GS. Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell 2007, 129:537-548. Abstract| PDF

Tsai J, Tong Q, Tan G, Chang A, Orkin S, Hotamisligil, GS. The transcription factor GATA2 regulates differentiation of brown adipocytes. EMBO Reports 2005, 6(9):879-884. Abstract | PDF

Tong Q, Tsai J, Tan G, Dalgin G, Hotamisligil GS. Interaction between GATA and C/EBP family of transcription factors is critical in GATA-mediated supression of adipocyte differentiation. Mol Cell Bio 2005, 25(2): 706-715. Abstract | PDF

Tong, Q and Hotamisligil, GS. Molecular mechanisms of adipocyte differentiation. Reviews in Endocrine Met Disorders 2001, 2:349-355. Abstract| PDF

Nisoli E, Briscini L, Giordano A, Tonello C, Wiesbrock SM, Uysal KT, Cinti S, Carruba MO, Hotamisligil GS. Tumor necrosis factor alpha mediates apoptosis of brown adipocytes and defective brown adipocyte function in obesity. Proceedings of the National Academy of Sciences of the United States of America. 97(14):8033-8, 2000. Abstract | PDF

Tong Q, Dalgin G, Xu H, Ting CN, Leiden JM, Hotamisligil GS. Function of GATA transcription factors in preadipocyte-adipocyte transition. Science 290(5489):134-138, 2000. Abstract| PDF

Sethi JK, Xu H, Uysal KT, Wiesbrock SM, Scheja L, Hotamisligil GS. Characterisation of receptor-specific TNFalpha functions in adipocyte cell lines lacking type 1 and 2 TNF receptors. FEBS Letters. 469(1):77-82, 2000. Abstract | PDF