Hotamisligil Laboratory
Differentiation and Lineage Commitment of Adipocytes and Energy Metabolism
One of the most fundamental questions in biology is how cells
commit to specific lineages and regulate their terminal differentiation
program. To understand this process, we use adipogenesis as a model system and
study the molecules that control early stages of differentiation in these
cells. We have recently 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.
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 theses 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.
Suggested reading from Hotamisligil Lab:
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
Tong, Q and Hotamisligil, GS.
Molecular mechanisms of adipocyte differentiation.
Reviews in Endocrine Met Disorders 2001, 2:349-355.
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
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
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
Gregor MF, Hotamisligil GS. Adipocyte
Stress: The endoplasmic reticulum and metabolic disease. Journal
of Lipid Research 2007, 48(9): 1905-144. Abstract | PDF