The expanding problem of adipose depot remodeling and postnatal adipocyte progenitor recruitment

Abstract

The rising incidence of obesity and associated metabolic diseases has increased the urgency in understanding all aspects of adipose tissue biology. This includes the function of adipocytes, how adipose tissue expands in obesity, and how expanded adipose tissues in adults can impact physiology. Here, we highlight the growing appreciation for the importance of de novo adipocyte differentiation to adipose tissue expansion in adult humans and animals. We detail recent efforts to identify adipose precursor populations that contribute to the physiological postnatal recruitment of white, brown, and beige adipocytes in mice, and summarize new data that reveal the complexity of adipose tissue development in vivo.

Keywords: Adipogenesis; Adipose precursors; Beige adipocytes; Brown adipocyte; Obesity; White adipocytes.

Figure 1. Distribution of White and Brown/Beige Adipose Tissue in Adults

White adipose tissue (WAT) is organized into distinct depots, classified by location as subcutaneous or intra-abdominal. The major subcutaneous WAT includes the abdominal, gluteal, and femoral depots. Other white subcutaneous depots include the cranial and facial adipose tissue. Intra-abdominal adipose tissue is located within the peritoneum and includes the omental, retroperitoneal, and visceral (mesenteric) fat. White adipocytes also accumulate in other locations, including behind the eye (retro-orbital), around joints (periarticular), in bone marrow, surrounding the heart (pericardial), and within the skeletal muscle (intramuscular). Brown adipose tissue (BAT) in adults exists as a heterogeneous tissue, containing brown and beige adipocytes interspersed with white adipocytes. BAT depots are located in the cervical, supraclavicular, and paravertebral regions in adults.

Figure 2. White Adipose Tissue Expansion in Obesity

Expansion of white adipose tissue in response to caloric excess occurs through the enlargement of existing adipocytes (hypertrophy) and/or through an increase in adipocyte number (hyperplasia). Pathologic expansion through hypertrophy of adipocytes is associated with inflammation, hypoxia, and fibrosis, with early onset of insulin resistance. Adipocyte dysfunction leads to the deleterious spillover of lipids into non-adipose organs, termed lipotoxicity. Healthy expansion through hyperplasia of adipose tissue occurs through the recruitment of preadipocytes and de novo adipocyte differentiation. This occurs alongside with angiogenesis and prevents or delays the onset of both insulin resistance and ectopic lipid accumulation.

Figure 3. Tracking Adipogenesis with the AdipoChaser Mouse Model

A) AdipoChaser mice utilize a combination of three published transgenic lines: 1) transgenic mice expressing the “tet-on” transcription factor rtTA under the control of the Adiponectin gene promoter, (“Adn-rtTA”), 2) a tet-responsive CRE (TRE-Cre) line that can be activated with rtTA in the presence of doxycycline, and 3) Rosa26 Reporter mice expressing β-galactosidase (LacZ) from the Rosa26 locus in a Cre dependent manner (Rosa26-loxP-STOP-loxP-LacZ). In the absence of doxycycline (Dox), there is no reporter expression in mature adipocytes. Upon treatment with doxycycline, rtTA activates the TRE promoter to induce Cre expression, and Cre protein will subsequently eliminate the floxed transcriptional stop cassette and permanently turn on reporter gene expression in every mature adipocyte present during doxycycline exposure. Any new adipocytes that develop after removal of Dox are derived from precursors, through de novo adipogenesis. B) “Pulse-Chase” lineage tracing using the AdipoChaser model has now been used to reveal depot-specific mechanisms of adipose expansion in obesity and the origin of inguinal beige adipocytes recruited upon cold exposure. Gonadal white adipose tissue (WAT) expands through enlargement of existing adipocytes (blue adipocytes) and by de novo adipogenesis (unlabeled adipocytes). Inguinal WAT mass expands only by adipocyte hypertrophy. Upon cold exposure, multilocular beige adipocytes emerge through de novo beige adipogenesis (unlabeled beige adipocytes) as well as via a conversion of existing adiponectin⁺ mature adipocytes (blue beige adipocytes).

Figure 4. Adipose Precursors Contributing to WAT Hyperplasia in Obesity

Recent pulse-chase lineage tracing studies reveal multiple adipocyte precursor populations involved in white adipose tissue (WAT) expansion in adult mice undergoing high-fat diet feeding (HFD). BrdU labeling experiments indicate that a stem cell-like population of adipose progenitor cells (CD24⁺; Sca1⁺; CD34⁺; Pdgfrα⁺; CD31⁻; CD45⁻) undergo rapid proliferation in response to HFD and differentiate into white adipocytes. The precise location(s) of these cells within the depot remain unclear. The abundance of highly committed population of perivascular (mural) preadipocytes (Pdgfrβ⁺; Pdgfrα⁺; CD34⁺; Sca1⁺; Zfp423⁺; Pparγ2⁺; CD24^+/−; CD31⁻; CD45⁻) increases upon HFD feeding. Genetic lineage tracing reveals mural Pdgfrβ+ cells contribute to adipocyte hyperplasia in this setting. Whether mural preadipocytes proliferate prior to differentiation is unclear as is whether the more primitive adult adipose progenitor passes through the perivascular stage during differentiation into the mature adipocyte. Other precursor populations that contribute to adipocyte hyperplasia in obesity may exist.