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Review
. 2014 Mar;1842(3):340-51.
doi: 10.1016/j.bbadis.2013.05.027. Epub 2013 Jun 4.

Adipocyte lineages: tracing back the origins of fat

Joan Sanchez-Gurmaches  1 , David A Guertin  2
Affiliations
Review

Adipocyte lineages: tracing back the origins of fat

Joan Sanchez-Gurmaches et al. Biochim Biophys Acta. 2014 Mar.

Abstract

The obesity epidemic has intensified efforts to understand the mechanisms controlling adipose tissue development. Adipose tissue is generally classified as white adipose tissue (WAT), the major energy storing tissue, or brown adipose tissue (BAT), which mediates non-shivering thermogenesis. It is hypothesized that brite adipocytes (brown in white) may represent a third adipocyte class. The recent realization that brown fat exist in adult humans suggests increasing brown fat energy expenditure could be a therapeutic strategy to combat obesity. To understand adipose tissue development, several groups are tracing the origins of mature adipocytes back to their adult precursor and embryonic ancestors. From these studies emerged a model that brown adipocytes originate from a precursor shared with skeletal muscle that expresses Myf5-Cre, while all white adipocytes originate from a Myf5-negative precursors. While this provided a rational explanation to why BAT is more metabolically favorable than WAT, recent work indicates the situation is more complex because subsets of white adipocytes also arise from Myf5-Cre expressing precursors. Lineage tracing studies further suggest that the vasculature may provide a niche supporting both brown and white adipocyte progenitors; however, the identity of the adipocyte progenitor cell is under debate. Differences in origin between adipocytes could explain metabolic heterogeneity between depots and/or influence body fat patterning particularly in lipodystrophy disorders. Here, we discuss recent insights into adipose tissue origins highlighting lineage-tracing studies in mice, how variations in metabolism or signaling between lineages could affect body fat distribution, and the questions that remain unresolved. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

Keywords: Adipocyte progenitor/precursor; Brite or beige adipocyte; Brown adipose tissue (BAT); Lipodystrophy; Myf5; White adipose tissue (WAT).

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Figures

Figure 1
Figure 1. The Myf5 lineage contribution to the precursor pool in each fat depot varies with its anatomical location
The contribution of the Myf5 lineage to the adipocyte precursor cell compartment (defined as CD31−CD45−Terr119−CD29+CD34+Sca1+ cells) was recently determined by lineage tracing with Myf5-Cre;R26R-YFP mice. More than 95% of the precursors in brown fat are labeled with Myf5-Cre. In the anterior subcutaneous WATs (including interscapular and axial WATs) nearly 50% of the precursors trace to Myf5+ precursors, and in the rWAT (a visceral WAT), the Myf5 precursors give rise to approximately 70% of the adipocyte precursor cell pool. In contrast, the Myf5 lineage contributes very little to the adipocyte precursor pool in ingWAT and pgWAT, which are 90-95% Myf5neg. The contribution of the Myf5 lineage to the intramuscular adipogenic precursor pool (defined with slightly different cell surface markers) is very low. Dotted line indicates the abdominal cavity. References provided in the text.
Figure 2
Figure 2. Deleting PTEN with Myf5-Cre models partial lipodystrophy
Deleting PTEN with Myf5-Cre causes lipohypertrophy of the fat depots largely derived from Myf5+ adipocyte precursors (labeled in blue) and lipoatrophy of the fats that are largely Myf5neg (labeled in red). The overgrown fats are bigger because they contain more cells due to expansion of the Myf5+ adipocyte precursor cell population (not shown) and bigger cells as a result of increased lipid content (see histology insets). The absent fats are reduced to fibrotic tissue. This body fat distribution phenotype resembles the pathology of a rare human lipodystrophy syndrome called Madelung’s disease.
Figure 3
Figure 3. Where is Myf5-Cre expressed during adipocyte development?
At least two models could explain the origins of adipocytes that trace to Myf5-Cre+ precursors. (I) In the “common origin model”, Myf5+ (and possibly Pax3+) adipocyte precursors originate in the central dermomyotome during embryonic development and give rise to adipocyte progenitor cells residing in the stromal vascular fraction of each depot. Both Myf5+ and Myf5neg lineages contribute to the adipocyte precursor cell pool (lin−CD29+CD34+Sca1+) to varying degrees in each depot; however in BATs, asWATs, and rWAT the Myf5+ lineage precursors appear to be preferentially selected to become adipocytes while in the ingWAT, pgWAT, and mWAT the Myf5neg lineage precursors selectively differentiate. (II) Alternatively, in the “selective induction model” Myf5neg precursors residing in the stromal vascular fraction of asWAT and rWAT (and perhaps even in BAT) induce Myf5-Cre (and possibly Pax3) expression upon differentiation giving rise to Myf5+ precursors, while in the other WATs Myf5-Cre is not induced. Whether Myf5 protein has a functional role in these adipocyte lineages is unknown.
Figure 4
Figure 4. A model based on recent lineage tracing studies that explains some of the complexity of adipocyte ancestry
A trending idea is that morphologically brown (multilocular), white (unilocular), and brite (interconvertible) adipocytes develop along unique lineages. However, recent studies in mice using Cre-Lox technology to irreversibly label cellular lineages argues that it is likely not this simple. An alternative view is that morphologically white adipocytes arise from multiple distinct lineages. One of these lineages is also marked by ancestral Myf5 expression and gives rise to morphologically brown adipocytes, a subset of morphologically white adipocytes (e.g. in the asWAT and rWAT), skeletal muscle cells, dermis, and ribs. Some of the Myf5-positive lineage derived white adipocytes become brite adipocytes when stimulated (e.g. Myf5-positive lineage white adipocytes in rWAT and asWAT). Other markers such as Engrailed-1 might also express early in this lineage. Whether the Myf5 lineage derived brown and white adipocytes arise from the same precursor is still unknown. Most white adipocytes in ingWAT and pgWAT develop from a Myf5-negative lineage (or possibly multiple lineages). Some of these Myf5-negative lineage white adipocytes can also become brite when stimulated (e.g. the Myf5-negative lineage white adipocytes that undergo interconversion in the ingWAT). Some brite adipocytes might also originate from a lineage distinct from the other white adipocytes although a Cre driver unique to a brite adipocyte lineage has not been found. Although white/brite adipocyte lineages are just beginning to be defined, PDGFRα appears to express in the ingWAT, pgWAT, rWAT, and mesenteric WAT lineages. Importantly, when each lineage mark actually expresses, when the lineages diverge during development, and the earliest common mesenchymal progenitor cell remain unclear and this is indicated by dotted lines and question marks. Another distinct white adipocyte lineage arises from Sox10 and Wnt1-expressing neural crest precursors in the cephalic region of young mice (notably, an unidentified lineage begins replacing neural crest derived cephalic adipocytes with age). These adipocytes label positive for PDGFR-α+ by antibody staining and therefore likely would trace with PDGFR-Cre, although this has not been shown. In sum, the emerging lineage tracing data presents a complex picture of adipocyte origins. iBA, sBA, cBA = interscapular, subscapular, and cervical brown adipocyte; asWA, rWA, pgWA, ingWA = anterior subcutaneous, retroperitoneal, perigonadal, inguinal white adipocyte. For more detailed information see [50, 51, 83, 100, 103, 114, 116, 127].
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