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	Figure 1. Life cycle of adipocytes. Adipogenesis describes the process by which adipose progenitors differentiate into lipid‐filled unilocular lipid droplet. These newly differentiated small adipocytes gradually accumulate more lipid over time. When they become too large, they often die and the lipid is cleared by macrophages, resulting in tissue inflammation and adipocyte dysfunction. When adipocytes reach a critical or maximum size, they are hypothesized to trigger signals to recruit and differentiate adipogenic progenitors. The mean age of adipocytes in humans is reported to be ∼2 (349) to 10 years (346).
	Figure 2. Major adipose depots in humans. Major SATs are abdominal (superficial and deep), gluteal and femoral. Intra‐abdominal depots include visceral (omental, mesenteric, and epiploic that are associated with digestive organs) as well as retroperitoneal and perinephric (left panel). There are also smaller white depots associated with other organs and BATs, as illustrated (right panel).
	Figure 3. Schematic presentation of ASC isolation and their in vitro culture. ASCs can be isolated by collagenase digestion of adipose tissue from rodents and humans, followed by centrifugation to separate the SVF pellet, which contains ASCs, from the floating mature adipocytes. Adipose progenitors can be isolated from the SVF using various combinations of cell surface markers. Once plated and cultured, ASCs acquire fibroblast morphology and can be differentiated into adipocytes. Dedifferentiated fat (DFAT) cells are obtained from primary mature adipocytes through ceiling culture and they are morphologically similar to ASCs. Images of human primary adipocytes, cultured ASCs/preadipocytes, and DFAT cells are shown.
	Figure 4. Adipogenesis is regulated by multiple transcription factors. Arrow represents a time‐line of commitment to an adipogenic lineage and differentiation. Different transcription factors act at early and later stages of differentiation. Different colored progenitors indicate different lineages that may coexist within a depot. Details are presented in the text.
	Figure 5. Temporal expression pattern of adipogenic factors during differentiation of human ASCs. Human subcutaneous ASCs were differentiated following the published protocol (192). mRNA expression levels of adipogenic markers, C/EBPβ, C/EBPα, PPARγ, and LPL, are measured before and at indicated time points during differentiation and data are presented as % of the value on day 10 after differentiation. Mean of four independent experiments using nonpooled ASCs from four donors is presented.
	Figure 6. Factors that positively and negatively regulate adipogenesis. Adipogenesis is regulated by numerous autocrine, paracrine, and endocrine factors. Conflicting results on growth hormone and vitamin D have been reported.
	Figure 7. TGFβ superfamily members modulate adipogenesis. BMP stimulates while TGFβ inhibits adipogenesis by signaling through different Smad proteins. BMP signaling enhances adipogenesis by increasing the expression of PPARγ through the Smad1/5/8 mediated mechanism and by enhancing the transcriptional activity of PPARγ though the p38 MAPK pathway. TGFβ inhibits adipogenesis through the Smad2/3 mediated suppression of C/EBPβ and δ transcriptional activity.
	Figure 8. Insulin regulation of adipogenesis. Insulin enhances adipogenesis through AKT‐mediated phosphorylation of forkhead transcription factors which leads to their exclusion from the nucleus and hence inhibition of PPARγ transcriptional activity. Insulin induces SREBP1c expression, which leads to induction of lipogenic genes and lipid accumulation. Short‐term ERK1/2 activation is stimulatory while long term is inhibitory to adipogenesis.
	Figure 9. Excess glucocorticoids promote adipogenesis over osteoblastogenesis. The balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells (MSCs) is regulated by several hormones, growth factors, and their downstream signaling cascades. In general, many factors specify MSCs to a lineage at the expense of the other. However, GCs have been shown to promote both adipogenic and osteogenic commitment, depending on the concentrations. High GCs promote adipogenesis of MSCs at the expense of osteoblastogenesis via upregulation of adipogenic transcription factors, C/EBPs and PPARγ. Low GCs improve osteoblastogenesis by increasing the WNT signaling and expression of osteogenic factors, RUNX2 and OSX.
	Figure 10. Glucocorticoids regulate adipogenesis through multiple mechanisms. GC signaling is regulated at the prereceptor level by 11βHSD1 and 2, which activate and inactivate cortisol, respectively. Once bound to the active ligand, GR translocates into the nucleus where it induces the expression of proadipogenic factors, C/EBPs and PPARγ and suppresses Pref‐1, an antiadipogenic factor, stimulating adipogenesis. The molecular mechanisms through which excess GCs lead to visceral adiposity are beginning to be elucidated. GCs increase adipogenesis in male gonadal through suppression of ADAMST1 (407). In addition, LMO3 has been suggested as a visceral specific molecular partner for GCs in human, but not in rodent, ASCs (209).
	Figure 11. Estrogen regulation of preadipocyte proliferation and differentiation. Results from majority of studies indicate that estrogen enhances proliferation, although cell‐type dependent inhibitory effects are reported. Estrogen enhancement of preadipocyte proliferation is reported to be greater in ASCs from females than males and subcutaneous than intra‐abdominal depots. Although contradictory results are obtained from in vitro studies for the estrogen effects on adipogenesis, results from rodent models indicate that estrogen normally has an inhibitory effect on overall adiposity in both sexes.
	Figure 12. Androgen regulation of preadipocyte proliferation and differentiation. Androgens dose‐dependently affect ASC proliferation; no effects at low concentration and inhibition at high concentration. In vitro, androgens consistently suppress adipogenesis with greater effects in ASCs from intra‐abdominal than SAT.
	Figure 13. Sex‐dependent depot differences in adipose tissue remodeling. Adipose expansion through hypertrophy or hyperplasia influences adipose tissue health and systemic metabolism. A limited capacity to expand through hyperplasia may cause excess hypertrophy of existing adipocytes, which eventually leads to adipocyte death, adipose inflammation, and excess remodeling. In contrast, some depots can expand through hypertrophy followed by hyperplasia. Male gonadal tends to follow the first pattern, while subcutaneous depots in both sexes and female depots tend to follow the second.

Teaching Material

M. -J. Lee. Hormonal Regulation of Adipogenesis. Compr Physiol 7: 2017, 1151-1195. doi:10.1002/cphy.c160047

Didactic Synopsis

Major Teaching Points:

1. Excessive caloric intake leads to adipocyte hyperplasia and hypertrophy and there are sex-dependent depot differences in adipose expansion capacity.
2. New adipocyte development occurs through the recruitment of adipose progenitors and their differentiation into adipocytes.
3. Adipogenesis is regulated by complex array of transcription factors and numerous autocrine, paracrine, and endocrine signals.
4. Proadipogenic factors include glucocorticoids, BMPs, insulin/IGF-1 and thyroid hormone.
5. Known antiadipogenic factors are TGFβ family (TGFβ, Activin A, and CTGF), WNTs (WNT5A and WNT10B), and sex-steroids hormones (estrogen and androgens).
6. Glucocorticoids and sex steroid hormones are known to depot-dependently affect body fat accumulation and adipocyte development.
7. Data from in vitro experiments and in vivo models are not always consistent. The actions of hormones on adipose tissue cellularity in vivo are complex and often confounded by their effects on energy intake and expenditure.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Adipogenesis describes the process by which adipose progenitors are committed to adipogenic lineage and then, fully differentiate into lipid-filled adipocytes. Adipocytes turn over throughout adulthood such that when adipocytes become too large, they die and are replaced by new adipocytes. The turnover rates of human adipocytes are reported to be ~2 (349) to 10 years (346).

Figure 2. Teaching points: Adipose tissues are present in multiple locations in humans, both in subcutaneous or intra-abdominal areas. Major subcutaneous adipose tissues are abdominal, gluteal and femoral, and intra-abdominal depots are omental (hangs off stomach), mesenteric (surrounds small intestine), epiploic (surrounds large intestine), and retroperitoneal and perinephric (around kidney). Depot differences in their developmental origins, functions, and expansion and remodeling capacity have been elucidated.

Figure 3. Teaching points: ASCs can be isolated by collagenase digestion of adipose tissue. Based on density, ASCs containing stromal cells are separated from the floating mature adipocytes and can be further isolated based on their cell surface markers. Once plated and cultured, ASCs acquire fibroblast morphology and can be differentiated into adipocytes. DFAT cells are obtained from primary mature adipocytes through “ceiling culture.” DFAT cells are morphologically similar to ASCs and can be differentiated to adipocytes. Imagesof human primary adipocytes, cultured ASCs/preadipocytes, and DFAT cells are shown.

Figure 4. Teaching points: Adipogenesis is regulated by multiple factors that act different stages of differentiation. Positive and negative regulators of adipogenesis are presented.

Figure 5. Teaching points: Adipogenic factors exhibit temporal expression pattern during differentiation of human preadipocytes. mRNA expression levels of adipogenic markers, C/EBPβ, C/EBPα, PPARγ, and LPL, are measured before (0’) and at indicated time points (3 h, 1 day, 3 days, 6 days, and 10 days) during differentiation and data are presented as % of the value on day 10.

Figure 6. Teaching points: Adipogenesis is regulated by numerous factors that act through autocrine, paracrine, and endocrine manners. Proadipogenic factors include GCs, BMP2/4/7, insulin/IGF-1 and T3. Known antiadipogenic factors are TGFβ family (TGFβ, Activin A, and CTGF), WNTs (WNT5A and WNT10B), and sex-steroids hormones (estrogen and androgens). The effects of GH and vitamin D on adipogenesis have been inconsistent.

Figure 7. Teaching points: BMPs exert their biological effects through the activation of type I (BMPIR) and type II (BMPIIR) receptors. Upon binding of BMPs, BMP receptors phosphorylate and activate Smad1/5/8. Phosphorylated Smad1/5/8 associates with Smad4 and then, translocate to the nucleus and regulates expression of target genes including PPARγ, a mater regulator of adipogenesis. BMP family members also use the p38 MAPK pathway to regulate PPARγ activity. TGFβ binds to TGFBR1 and R2, which in turn phosphorylate downstream transcription factors, Smad2 and Smad3. Phosphorylated Smad2 or Smad3 binds to Smad4 and translocates to the nucleus and regulates gene transcription. TGFβ are known to inhibit adipogenesis through the Smad2/3-mediated suppression of C/EBPβ and δ transcriptional activity.

Figure 8. Teaching points: Insulin enhances adipogenesis through AKT-mediated phosphorylation of forkhead transcription factors. Phosphorylated forkhead transcription factors are excluded from the nucleus, which leads to enhancement of PPARγ transcriptional activity. Insulin induces SREBP1c expression and thus, induction of lipogenic genes and lipid accumulation. Insulin signaling through the ERK1/2 MAPK pathway may be also involved in adipogenesis. However, the effects of the ERK1/2 activation on adipogenesis have been inconsistent; short-term ERK1/2 activation is stimulatory, while long-term activation is inhibitory.

Figure 9. Teaching points: MSCs can be committed to adipogenic or osteogenic lineages. While many factors are known to commit MSC to a lineage at the expense of the other, GCs have been shown to promote both adipogenic and osteogenic lineage commitment, depending on the concentrations. High GCs promote adipogenesis of MSCs by upregulating expression of adipogenic transcription factors, C/EBPs and PPARγ. In contrast, low GCs improve osteoblastogenesis by increasing the WNT signaling and expression of osteogenic transcription factors, RUNX2 and OSX.

Figure 10. Teaching points: Intracellular cortisol availability is regulated by 11βHSD1 and 2, which activates and inactivates cortisol, respectively. Upon binding to the active form, cortisol, the GR translocates into the nucleus and regulates the expression levels of many adipogenic factors. Both GC-mediated induction of C/EBPs and PPARγ (proadipogenic factors) and suppression of Pref-1 (an antiadipogenic factor) are involved in the GC enhancement of adipogenesis. GCs have been shown to increase adipogenesis in visceral depots specifically by suppressing ADAMST1 (an antiadipogenic factor) in gonadal depot in mice (407) and enhancing LMO3 (a proadipogenic factor) in omental depot in humans (209).

Figure 11. Teaching points: Estrogen is known to increases proliferation of preadipocytes, depot, and sex dependently. Estrogen-mediated enhancement of preadipocyte proliferation is reported to be greater in females than males and subcutaneous than intra-abdominal depots. Controversial results are obtained from in vitro studies testing the effects of estrogen on adipogenesis are inconsistent. Data from in vivo models indicate that estrogen may have an inhibitory effect on overall adiposity in both sexes.

Figure 12. Teaching points: Androgens dose-dependently affect proliferation of preadipocytes; no effects on proliferation at low concentration or inhibition at high concentration. Data from in vitro experiment consistently show that androgens suppress adipogenesis with greater effects in ASCs from intra-abdominal than subcutaneous depots.

Figure 13. Teaching points: Adipose tissues expand through increasing the number (hyperplasia) or size (hyperplasia) of adipocytes and expansion through hyperplasia is thought be beneficial for adipose tissue health and systemic metabolism. Sex-dependent depot differences in adipose expansion capacity are noted in the mouse models. Male gonadal depot expands mainly through hypertrophy of existing adipocytes, which eventually leads to adipocyte death, adipose inflammation, and excess remodeling. In contrast, female adipose depots and inguinal in both sexes are thought to expand through both hypertrophy and hyperplasia and are less inflammatory. Accordingly, age-matched male versus female mice are more susceptible to insulin resistance caused by HFD-induced obesity.