Roles for bone marrow-derived cells in adipose tissue expansion during development and diet-induced and genetic models of obesity

Authors: STRISSEL, KATHERINE - JM USDA HNRCA -TUFTS UNIV; SHAUL, MERAV - JM USDA HNRCA -TUFTS UNIV; Greenberg, Andrew; Obin, Martin

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 4/23/2008
Publication Date: 5/22/2008
Citation: Strissel, K.J., Shaul, M.E., Greenberg, A.S., Obin, M. 2008. Roles for bone marrow-derived cells in adipose tissue expansion during development and diet-induced and genetic models of obesity. NIH Workshop: Establishment, Maintenance, & Turnover of Fat Depots. Paper No. 42.

Interpretive Summary:

Technical Abstract: Adipose tissue (AT) expansion is a highly-regulated process of tissue remodeling and repair involving angiogenesis, matrix and cellular turnover, and stem cell recruitment and differentiation. Recent studies in both humans and mice have revealed the complex involvement of macrophages and other bone marrow-derived cells in adipose tissue remodeling. Distinct patterns of adipose tissue expansion involving different subsets of bone marrow-derived cells have been described in ‘normal’ adipose tissue growth and in mouse models of obesity. These include: 1) distal growth of epididymal AT requiring LYVE-1+ M-phis and formation of a dense vascular network (DVN) (lean and obese C57BL/6 mice) (Cho et al, 2007), 2) adipogenic/angiogenic clusters of CD68+,CD34+ lectin binding stromal cells in epididymal AT (8 week and 30 week db/db mice) (Nishimura et al, 2007), and 3) F4/80+ M-phis within crown-like structures (CLS) involved in adipocyte turnover (HFF C57BL/6 mice, db/db mice, lean HSL-/- mice) (Cinti et al, 2005; Strissel et al, 2007, Nishimura et al, 2007, 2008). Although distinct, these processes have been observed concurrently within the same depot (i.e., processes 2 and 3 in ob/ob and db/db mice). However, processes 1 and 2 appear to predominate during the hyperplastic phase of adipose tissue growth in young mice and following massive epididymal depot turnover resulting from long-term HFF (Strissel et al, 2007). Tissue remodeling is typically an inflammatory process. We recently provided evidence that M-phi-mediated clearance of dead adipocytes during HFF is associated with the phenotypic switch of ATM-phis to a CCR2+/CD11c+ subtype (Lumeng et al, 2006), the expression of M1 cytokines, and the development of systemic insulin resistance (Strissel et al, 2007). Our laboratory is now addressing the following questions: 1) Which expansion processes (#s 1-3 above) are utilized during “normal” AT growth and during HFF-induced obesity 2) Which processes are pro-inflammatory? 3) Do depot differences in AT expansion processes correlate with differences in inflammation and pathogenicity observed between visceral and subcutaneous AT? To address these questions we have mapped the expression of immune cell and precursor cell markers (Mac-2, F4/80, CD68, LYVE-1, CD45, CD34, CD31, CD11c and CCR2) and M1 and M2 cytokines (TNFa and IL-6; TGF-beta1 and IL-10) in epididymal and inguinal subcutaneous AT 1) during AT growth in post-natal maturation 2) in 8 week old db/db mice, and 3) during a 5 month time course of HFF. Results demonstrate that Distal growth / DVN formation (process 1) and clearance of dead adipocytes by CLS M-phis (process 2) are both associated with TNF-alpha gene upregulation in F4/80+ CCR2+ cells. Bone marrow-derived precursors (CD34+, CD45+) also appear to upregulate TNF-alpha during distal growth. Adipogenic/angiogenic clusters characterized in db/db mice (process 2) are rare if not absent in the epididymal AT of HFF mice during adipose tissue expansion and the development of insulin resistance. However, adipogenic/angiogenic clusters are required for depot repair subsequent to massive adipocyte turnover observed after 4 months of HFF. Distal growth (process 1) and clearance of dead adipocytes by CLS M-phis (process 3) are not apparent during expansion of subcutaneous AT in response to HFF. These results are discussed in the context of depot differences in pre-existing tissue components (e.g., substratum, vasculature) and how the requirement for synthesizing tissue components de novo underlies the recruitment of inflammatory ATM-phis and precursors and the pro-inflammatory character of epididymal AT.