Prostaglandin D₂ and F_2α as Regulators of Adipogenesis and Obesity

Abstract

Prostaglandins (PGs) are lipid-derived autacoids that are synthesized from arachidonic acid by the action of cyclooxygenases and PG terminal synthases. PGs consist of PGD₂, PGE₂, PGF_2α, prostacyclin (PGI₂), and thromboxane A₂, which act through G protein-coupled receptors. PGs sustain homeostatic functions and exert a variety of pathophysiological roles to regulate the development of various diseases such as obesity and dyslipidemia. Adipocytes (fat cells) have the unique capacity to accumulate large amounts of lipids as energy source in lipid droplets. Adipogenesis is the process of differentiation from preadipocytes to mature adipocytes, which is regulated by various adipogenic transcription factors. Obesity is defined as an abnormal increase in adipose tissue mass and is considered to be a risk factor for the development of lifestyle-related diseases including cardiovascular disease, hyperlipidemia, and type 2 diabetes mellitus. This review summarizes insights into the roles of PGD₂, PGF_2α, and their synthases in the regulation of adipogenesis and obesity.

1. INTRODUCTION

Prostaglandins (PGs) are lipid mediators and cyclic oxygenated fatty acids with 20-carbons. PGs were discovered in the 1930s as regulators of blood pressure and smooth muscle contraction.¹⁾ PGs are derived from arachidonic acid, which is liberated from the phospholipids of membranes by the action of cytosolic phospholipase A₂ (cPLA₂) (Fig. 1). Arachidonic acid is metabolized to PGG₂ by PG-endoperoxide synthases (PTGSs): cyclooxygenase (COX)-1 and COX-2.²⁾ The COX enzymes further convert PGG₂ to PGH₂, a common precursor for the synthesis of PGD₂, PGE₂, PGF_2α, prostacyclin (PGI₂), and thromboxane A₂ (TXA₂), which are synthesized by their specific PG synthases.³⁾ Moreover, many metabolites of PGs and fatty acids have been identified using high-sensitivity LC/MS.⁴⁾ The structural differences between PGs and their metabolites account for their various biological activities. PGs are produced on demand in almost every tissue of the body and have a variety of characteristics such as cell-specific and time-specific manners. They can act in an autocrine manner, stimulating the same tissue (cell) in which they are produced, or in a paracrine manner, stimulating local tissues (cells) proximal to where they are secreted. PGs exert their physiological roles by binding to their specific G protein-coupled receptors (GPCRs), which are classified into nine subfamilies (DP1, CRTH2/DP2, FP, EP1–4, IP, and TP receptors).⁵⁾

Fig. 1. PG Biosynthesis and Regulation of Adipogenesis by PGs

“Pre” indicates adipocyte precursor cells. “Early,” “middle,” and “late” mean early, middle, and late stage of adipogenesis, respectively. Red arrowheads indicate “activation,” and black blunt end lines mean “suppression.”

PGs are associated with the regulation of various physiological processes and diseases. PGD₂ is involved in the control of sleep, pain, hypertension, cardiovascular diseases, appetite, obesity, and diabetes.⁶⁾ PGF_2α is known to regulate the contraction of the uterine muscles, the ocular system, and obesity.⁷⁾

Obesity is a worldwide epidemic and is associated with the development of lifestyle-related diseases such as cardiovascular disease, type 2 diabetes mellitus, hypertension, and cancer.^8–11) Obesity is a complex medical condition characterized by the accumulation of abnormal fat, in most cases as a result of increased food intake and/or decreased exercise.¹²⁾ Accumulation of excessive adipose tissue is attributed to both an increased number (hyperplasia) and enlarged size (hypertrophy) of adipose cells.

Adipose tissue is a specialized connective tissue consisting mainly of adipocytes (fat cells, adipose cells). Adipocytes are involved in the control of energy homeostasis by storing large amounts of triacylglycerol during periods of energy excess and mobilization of these lipids during nutritional deficiencies.^9–11) Adipogenesis (adipocyte differentiation) is a process of proliferation and differentiation of adipocyte precursor cells (preadipocytes) to mature adipocytes, which is controlled via complex processes, including coordinated changes in various physiological events, such as hormone sensitivity and gene expression.¹³⁾

PGs are secreted from adipose tissue and are involved in both positive and negative regulation of obesity progression (adipogenesis).¹⁴⁾ PGI₂ promotes the progression of adipocyte differentiation of preadipocytes through PGI₂ receptors (IP) by elevating the expression of CCAAT/enhancer binding protein (C/EBP) β and δ, both of which are important transcription factors in the activation of the early stage of adipogenesis.^15,16) They subsequently activate the expression of peroxisome proliferator-activated receptor (PPAR) γ, which is a critical transcription factor in adipogenesis to promote adipocyte maturation. PGI₂ enhances high-fat diet (HFD)-induced obesity through IP receptors in adipocytes.¹⁷⁾ PGD₂ and its non-enzymatic metabolites, including Δ¹²-PGJ₂ and 15-deoxy Δ^12,14-PGJ₂ (15d-PGJ₂), activate adipogenesis through chemoattractant receptor homologous molecule expressed on type 2 T helper (Th2) cells (CRTH2/DP2 receptors) and PPARγ.^18–21) In contrast, PGF_2α and PGE₂ suppress the early stage of adipogenesis by increasing the COX-2-mediated production of PGF_2α and PGE₂ through their respective receptors.²²⁾

The roles of PGs and their molecular mechanisms in the control of adipogenesis and obesity have been well-studied. In this review, I summarize the recent progress in the functions of PGD synthase (PGDS)/PGD₂ and PGF synthase (PGFS)/PGF_2α in the regulation of adipogenesis and various metabolic disorders, such as obesity and dyslipidemia.

2. PGDS/PGD₂/DP RECEPTORS

PGD₂ regulates a variety of physiological events including the promotion of sleep and bronchoconstriction, inhibition of platelet aggregation, and relaxation of smooth muscle contraction.^6,23)

PGD₂ is produced by the isomerization of the 9,11-endoperoxide group of PGH₂ by the action of two distinct types of PGDSs: lipocalin-type PGDS (L-PGDS) and hematopoietic PGDS (H-PGDS).^6,24) L-PGDS, also known as β-trace protein, is abundantly expressed in meningeal and epithelial cells of the choroid plexus and oligodendrocytes of the brain, in epithelial cells of the epididymis, and in Leydig cells of the testis.²⁵⁾ L-PGDS is a member of the lipocalin superfamily, a group of secretory proteins, which bind to and transport small lipophilic molecules.⁶⁾ Thus, L-PGDS is a multi-functional protein with PGD₂-synthesizing activity and transporter ability for small lipophilic molecules. The other PGDS, H-PGDS, is a member of Sigma class glutathione S-transferase family²⁶⁾ and is mostly responsible for the biosynthesis of PGD₂ in immune and inflammatory cells, such as mast cells,²⁷⁾ antigen-presenting cells,²⁸⁾ and Th2 cells.²⁹⁾ Moreover, PGD₂ is further metabolized to J-series PGs including PGJ₂, Δ¹²-PGJ₂, and 15d-PGJ₂.³⁰⁾

PGD₂ exerts its physiological effects through two PGD₂ receptors, DP1 receptors and CRTH2/DP2 receptors, which are coupled with G_S and G_i proteins, respectively.^5,31)

3. PGDS AND PGD₂ IN ADIPOGENESIS AND OBESITY

3.1. PGDS and PGD₂ in Adipogenesis

PGD₂ is synthesized by L-PGDS in mouse adipocyte 3T3-L1 cells, and its production increases during adipogenesis.³²⁾ L-PGDS expression is increased in adipocytes, and produces more PGD₂, which enhances the accumulation of intracellular lipids in adipocytes.^32,33) Knockdown of the expression of Ptgds, encoding L-PGDS, by small interfering RNA (siRNA) suppresses the differentiation of adipocytes derived from human mesenchymal stromal cells³⁴⁾ and 3T3-L1 cells.³²⁾ The exogenous addition of L-PGDS induces adipocyte differentiation.³⁴⁾

CRTH2/DP2 receptors, but not DP1 receptors, are predominantly expressed in 3T3-L1 cells.²⁰⁾ CAY10595, a CRTH2/DP2 receptor antagonist, but not BWA868C, a DP1 receptor antagonist, lowers the PGD₂-induced accumulation of intracellular triacylglycerol. 15R-15-Methyl PGD₂, a CRTH2/DP2 receptor agonist, enhances adipogenic and lipogenic gene expression. Moreover, 15R-15-methyl PGD₂ decreases glycerol release by inhibiting cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of hormone-sensitive lipase (HSL), a key enzyme in lipolysis.²⁰⁾ Lipolysis is enhanced in adipocytes that are differentiated from embryonic fibroblasts of Ptgdr2 (CRTH2/DP2 receptor) gene knockout (KO) mice, indicating that L-PGDS-produced PGD₂ inhibits the lipolysis via suppressing the cAMP-PKA-HSL signaling via CRTH2/DP2 receptors in adipocytes.²⁰⁾

PGD₂ is dehydrated to PGJ₂, Δ¹²-PGJ₂, and 15d-PGJ₂, spontaneously or in the presence of albumin. 15d-PGJ₂ has been identified as a ligand for PPARγ.^19,21) Δ¹²-PGJ₂ is a dominant PGD₂ metabolite in adipocytes, and enhances adipogenesis via PPARγ.^18,35) Therefore, PGD₂ enhances adipocyte differentiation through PPARγ-dependent and -independent (CRTH2/DP2 receptors) pathways (Fig. 2).

Fig. 2. Activation of Adipogenesis by L-PGDS-Produced PGD₂ through PPARγ-Dependent and -Independent (CRTH2/DP2 Receptors) Pathways in Adipocytes

Red arrowheads indicate “activation,” and black blunt end line means “suppression.” TG: triacylglycerol.

The transcriptional regulation of the Ptgds gene in adipocytes has been studied. Sterol regulatory element-binding protein-1c (SREBP-1c) and liver X receptor (LXR) are involved in the promotion of Ptgds gene expression in 3T3-L1 cells.³²⁾ The former is activated by fatty acids and the latter is activated by oxygenated derivatives of cholesterol (oxysterol), suggesting that Ptgds gene expression is regulated by fatty acids and cholesterols in adipocytes. Moreover, glucocorticoids induce the expression of Ptgds, and L-PGDS activates leptin expression in adipocytes which have been differentiated from mouse inguinal adipose stromal vascular fraction (SVF).³⁶⁾ Ptgds siRNA and AT56, an L-PGDS inhibitor, repressed glucocorticoid-induced leptin production, suggesting that the glucocorticoid-L-PGDS-leptin axis may be involved in the controlling PGD₂-mediated adipogenesis.³⁶⁾

3.2. PGDS and PGD₂ in Obesity

Ptgds gene-manipulated mice displayed various abnormalities in the regulation of lipid metabolism and obesity. However, the role of L-PGDS in obesity and obesity-related diseases is still controversial (Table 1).

Table 1. Obesity-Related Phenotypes of PGDS-Gene Manipulated Mice

Gene-manipulated mice	Obesity-related phenotype	Reference
Ptgds KO	Adipocyte size ↑	37)
	Glucose intolerance ↑, Insulin resistance ↑	38)
	Body weight ↑	39)
	Adipocyte hypertrophy ↑	40)
	Glucose intolerance ↑, Insulin resistance ↑
	Body weight →	44)
Hpgds TG	Body weight ↑	41)
Adipocyte-specific	Body weight ↓	45)
Ptgds KO	Insulin resistance ↓

Upward arrow: Increased; Downward arrow: Decreased; Horizontal arrow: Unchanged. TG: transgenic (overexpression).

The adipose size in adipose tissue of Ptgds KO mice is larger than that of wild-type mice under a low-fat diet (LFD) and HFD.³⁷⁾ Ptgds KO mice exhibit glucose intolerance and insulin resistance, with the decreased insulin-induced glucose incorporation.³⁸⁾ Moreover, Ptgds KO mice show increased body weight gain and adipose size in the subcutaneous and visceral adipose tissues under HFD.³⁹⁾ In addition, Ptgds KO mice have elevated aortic thickness, which is related to atherosclerosis,³⁷⁾ and increases atherosclerotic lesions in the aorta.³⁹⁾ Ptgds KO mice exhibit adipocyte hypertrophy and impaired glucose tolerance and insulin sensitivity under HFD conditions.⁴⁰⁾

In contrast, human H-PGDS-transgenic (TG; i.e., overexpressing) mice, which produce large amounts of PGD₂ in numerous tissues including adipose tissue, show increased body weight gain under HFD.⁴¹⁾ Furthermore, Ptgs2 (encoding COX-2) KO mice show decreased adipose tissue mass in the epididymis, and the levels of PGD₂ and 15d-PGJ₂ are reduced in adipose tissue.⁴²⁾ BW245C, a DP1 receptor agonist inhibits body weight gain in Apoe (encoding apolipoprotein E) KO mice, which correlates with a significant reduction in food intake.⁴³⁾ Ptgds KO mice show no significant change in body weight, but display improved glucose tolerance under HFD.⁴⁴⁾ This discrepancy in the roles of L-PGDS in adipose tissue may be due to a variety of physiological functions of PGD₂ and the broad expression of L-PGDS in the body.²⁵⁾ Thus, it may not be appropriate to disrupt Ptgds in the entire mouse body to elucidate the local functions of L-PGDS and PGD₂.

To address these concerns, we recently investigated the adipose-specific roles of L-PGDS and PGD₂ using Cre-loxP-mediated adipose-specific Ptgds KO mice under the control of fatty acid binding protein 4 (Fabp4, also known as aP2)-Cre transgene (Fabp4-Cre/Ptgds^flox/flox). In HFD-fed Fabp4-Cre/Ptgds^flox/flox mice, body weight gain, adipocyte size, and cholesterol and triacylglycerol levels in serum decreased, and impaired expression of adipogenic, lipogenic, lipolytic, and M1 macrophage marker genes was observed in white adipose tissue (WAT).⁴⁵⁾ In addition, PGD₂ levels in adipose tissue were decreased and insulin sensitivity was improved in Fabp4-Cre/Ptgds^flox/flox mice under HFD, compared with LFD, indicating that adipose-specific L-PGDS-produced PGD₂ increases body weight gain and promotes insulin resistance under HFD conditions⁴⁵⁾ (Fig. 3). Therefore, adipocyte-specific inhibition of L-PGDS and CRTH2/DP2 receptors may be useful for the treatment of obesity and obesity-mediated insulin resistance.

Fig. 3. L-PGDS/PGD₂-Induced Body Weight Gain and Insulin Resistance with the Altered Expression of Adipogenic, Lipogenic, Lipolytic, and M1 Macrophage Marker Genes/Proteins in Adipocytes of WAT in Mice under HFD Condition

Upward arrow: Increased; Downward arrow: Decreased; Horizontal arrow: Unchanged LPL: lipoprotein lipase; ACC: acetyl-CoA carboxylase; FAS: fatty acid synthase; SCD: stearoyl-CoA desaturase; ATGL: adipose triglyceride lipase; MGL: monoacylglycerol lipase; TG: triacylglycerol; DG: diacylglycerol; MG: monoacylglycerol.

L-PGDS expression is increased in brown adipose tissue (BAT) during cold exposure under HFD conditions.⁴⁴⁾ The expressions of lipogenic and thermogenic genes and norepinephrine-stimulated glucose uptake are enhanced in BAT of Ptgds KO mice, as compared with wild type mice, in a cold environment.⁴⁴⁾ Moreover, L-PGDS expression is elevated in BAT and subcutaneous WAT of Pparg (encoding PPARγ) KO mice.⁴⁶⁾ In Ptgds and Pparg double KO mice, the expressions of thermogenic, lipogenic, and lipolytic genes are reduced in subcutaneous WAT, compared with Pparg or Ptgds single KO mice, suggesting that L-PGDS and PPARγ coordinate to regulate lipid metabolism in adipose tissues.⁴⁶⁾

In ob/ob obese mice, Ptgds gene expression is decreased, but the expression of Hpgds (encoding H-PGDS) is increased in WAT.⁴⁷⁾ H-PGDS is expressed in macrophages and is involved in M2 polarization of macrophages in WAT, indicating that H-PGDS may be associated with anti-inflammatory effects in adipose tissues.⁴⁷⁾

In human subjects, microarray and quantitative PCR analyses demonstrated that PTGDS gene expression is increased in abdominal subcutaneous adipocytes isolated from obese individual than those from non-obese subjects.⁴⁸⁾ Moreover, the PTGDS gene is expressed in almost every tissue in the body²⁵⁾ and its expression level in omental adipose tissue is higher than in subcutaneous adipose tissue.⁴⁹⁾

In SNP analysis of the PTGDS gene in Japanese individuals, one SNP (rs6926) found in the 3′-untranslated region, was associated with serum high-density lipoprotein (HDL) cholesterol levels. Subjects with the A/A genotype of this SNP (rs6926) showed higher HDL-cholesterol levels in than those with A/C and C/C genotypes.⁵⁰⁾ The presence of the A/A genotype significantly reduces the risk for increased intima-media complex thickness of the carotid artery (C-IMTmax), which is associated with the development of carotid atherosclerosis in Japanese patients with hypertension.⁵⁰⁾

4. PGFS/PGF_2α/FP RECEPTORS

PGF_2α is produced in most tissues in the body⁵¹⁾ and plays an important role in many biological events, especially in the reproductive system, including ovulation, luteolysis, and contraction of uterine smooth muscle.⁵²⁾

PGF_2α is synthesized by reduction of either the 9,11-endoperoxide moiety of PGH₂ or the 9-keto group of PGE₂ in an nicotinamide adenine dinucleotide(NAD)(P)H-dependent manner. PGFS was first isolated from mammals as an enzyme that catalyzes the reduction of PGH₂ to PGF_2α, and PGD₂ to 9α,11β-PGF₂.⁵³⁾ Several aldo-keto reductase (AKR) family proteins have been identified as having PGFS activity.^54,55) AKR catalyzes the NAD(P)H-dependent reduction of a variety of carbonyl substrates, such as steroid hormones, monosaccharides, retinals, quinones, and PGs.^54,55) AKR1B1 (also known as aldose reductase)⁵⁶⁾ and AKR1C3 (also known as 17β-hydroxysteroid dehydrogenase type 5)⁵⁷⁾ in humans and AKR1B3 (also known as aldose reductase and ortholog of human AKR1B1),⁵⁸⁾ AKR1B7 (also known as vas deferens protein),⁵⁹⁾ AKR1B8 (ortholog of human AKR1B10),⁶⁰⁾ and AKR1B10 (identified as fibroblast growth factor-related protein 1 and identical to AKR1B16)^61,62) in mice have been identified as PGFSs. In addition, prostamide/PGFS has been identified as a novel PGFS in humans and mice.⁶³⁾

PGF_2α exerts its physiological functions by binding with FP receptors that are coupled with G_q protein,^5,64) which stimulates phospholipase C to increase intracellular Ca²⁺ levels and activate various kinases.^64–67)

5. PGFS AND PGF_2α IN ADIPOGENESIS AND OBESITY

5.1. PGFS and PGF_2α in Adipogenesis

PGF_2α suppresses adipocyte differentiation by modulating PPARγ activity via activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) 1/2 pathway through FP receptors.^68–74) The increased PGF_2α production in adipocytes is derived from enhanced Ptgs2 (COX-2) expression, which acts through a positive feedback loop that coordinately suppresses adipogenesis by elevating anti-adipogenic PGF_2α and PGE₂ production.²²⁾

In mice, AKR1B3 is abundantly expressed in adipocytes.⁷⁵⁾ Knockdown of Akr1b3 by siRNA decreases PGF_2α production and elevates adipogenesis in 3T3-L1 cells.⁶⁸⁾ This was abrogated by co-treatment with AL8810, an FP receptor antagonist, indicating that AKR1B3-produced PGF_2α inhibits adipogenesis through FP receptors in 3T3-L1 cells^68,69) (Table 2). AKR1B7 is also expressed in 3T3-L1 cells, and antisense Akr1b7 expression increases accumulation of intracellular lipids.⁵⁹⁾ However, transfecting cells with Akr1b8 and Akr1b10 siRNAs cause no significant effects on adipogenesis.⁶⁸⁾ Moreover, PGF_2α ethanolamide, a PGF_2α analog formed via anandamide which acts as a substrate for COX and is synthesized by prostamide/PGFS, inhibits the early stage of adipogenesis⁷⁶⁾ in 3T3-L1 cells.⁶⁹⁾

Table 2. Roles of PGFS and PGF_2α in Adipogenesis and Obesity in Mice

Gene (Protein)	Adipogenesis	Reference	Obesity (in KO mice)	Reference
Akr1b3 (AKR1B3)	Inhibition	68,69)	No effect	75)
Akr1b7 (AKR1B7)	Inhibition	59)	Increased adiposity	80)
Akr1b8 (AKR1B8)	No effect	68)	Not examined
Akr1b10 (AKR1B10)	No effect	68)	Not examined
Prxl2b (prostamide/PGFS)	Inhibition	76)	Not examined

In humans, AKR1B1 is a major PGFS in subcutaneous and omental adipose tissues⁷⁷⁾ and human multipotent adipose-derived stem (hMADS) cells.⁷⁸⁾ Ponalrestat, an inhibitor of aldose reductase (AKR1B1), decreases PGF_2α production and enhances adipocyte differentiation of hMADS cells.⁷⁵⁾ AKR1C3 activity is elevated by insulin in primary female subcutaneous adipocytes, but not in omental adipocytes.⁷⁹⁾ PGF_2α ethanolamide inhibits the early stage of adipogenesis in human subcutaneous adipocytes, as observed in mouse 3T3-L1 cells.⁷⁶⁾

5.2. PGFS and PGF_2α in Obesity

Akr1b3 KO mice do not show any significant effects on adipose tissue, although it is highly expressed in adipose tissue in wild-type mice.⁷⁵⁾ Akr1b7 KO mice show adiposity with hyperplasia and hypertrophy of adipocytes, with decreased production of PGF_2α in WAT.⁸⁰⁾ In vivo analyses of AKR1B8 and AKR1B10 have not been performed, although they are expressed in adipose tissues.⁷⁵⁾ However, it is difficult to analyze the function of AKR1B family proteins in mice, because the roles of AKR1B family proteins are redundant and the loss of function in one Akr1b KO mouse may be compensated by other AKR1B family proteins.⁸¹⁾

In humans, AKR1B1 predominantly produces PGF_2α in preadipocytes.⁷⁷⁾ In addition, women with high PGF_2α release in omental adipose tissue have high body mass index (BMI), waist circumference, homeostasis model assessment-insulin resistance (HOMA-IR), and AKR1B1 expression. Moreover, PGF_2α release by omental adipose tissue is increased in abdominally obese women.⁷⁷⁾ AKR1C3 expression is increased in subcutaneous and omental adipose tissues of women.⁸²⁾

However, the roles of PGF_2α and PGFS in the control of obesity and dyslipidemia have not been sufficiently analyzed in humans and mice. Ptgfr (encoding FP receptor) KO mice are useful for investigating the regulation of PGF_2α. Further studies are required to understand the functions of PGF_2α and PGFS in obesity and dyslipidemia in humans and mice.

6. CONCLUSION

PGs are associated with the regulation of many biological processes and diseases. Dysregulation of PG secretion causes an imbalance in homeostasis, which leads to the development of disorders. In this review, I discussed the roles of PGDS/PGD₂ and PGFS/PGF_2α in the regulation of adipogenesis and obesity, and highlight that these PG synthases and receptors are potential targets for the development of treating these disorders. In particular, it is noteworthy that the elucidation of the molecular and pathophysiological mechanisms underlying the actions of PGs lead to the development of strategies for the treatment of obesity and obesity-related diseases. Manipulating the genes of encoding PGDS and PGFS and their receptors in mice is useful for understanding the association between PGs and these disorders in mice. Moreover, pharmacological modulators of PG synthases and receptors will facilitate the development of novel therapeutic strategies for treating adipogenesis and obesity in the future. However, although PGDS and PGFS are potential therapeutic targets for these metabolic disorders, studies to date on the regulation of these disorders are insufficient. Thus, further studies in humans are needed to determine the potential of these strategies.

Acknowledgments

This work was supported in part by Grant-in-Aid for Scientific Research (16K08256, 20K07024) and Scientific Research on Innovative Areas (23116516) of Ministry of Education, Culture, Sports, Science and Technology (MEXT), and Grants from The Naito Foundation, The Japan Foundation for Applied Enzymology, and Daiwa Securities Health Foundation.

Conflict of Interest

The author declares no conflict of interest.

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