Nuclear Hormone Receptors and Adipogenesis

Gimble, Jeffrey M.; Robinson, Claudius E.; Clarke, Stephen; Hill, Molly R.

doi:10.1615/critreveukargeneexpr.v8.i2.30

Cited by 10 publications

(9 citation statements)

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“…To ensure that the presence of leptin receptors in our hBMSC preparations was not derived from contaminating adipocytes, the hBMSC cells were tested with Oil Red O staining for lipid droplets in the cytoplasm and analyzed for PPAR␥ mRNA expression. PPAR␥ is a nuclear receptor essential in adipocyte cell fate determination from stem cells (25). No Oil Red O-stained cells could be detected in our hBMSC cultures (Fig.…”

Section: Leptin Receptors (Ob-r) Were Expressed In Hbmsc-usingmentioning

confidence: 83%

Leptin Induces Apoptosis via ERK/cPLA2/Cytochrome c Pathway in Human Bone Marrow Stromal Cells

Kim

Hong

Kim

et al. 2003

Journal of Biological Chemistry

115

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Leptin, the Ob gene product, has emerged recently as a key regulator of bone mass. However, the mechanism mediating leptin effect remains controversial. Because the action of leptin is dependent on its receptors, we analyzed their expression in osteoblast-lineage primary human bone marrow stromal cells (hBMSC). Both the short and long forms of leptin receptors were detected in hBMSC. Leptin significantly decreased the viability of hBMSC. This cytotoxic effect was prevented by ZVal-Ala-Asp-fluoromethylketone, a pan-caspase inhibitor, implicating that leptin-induced hBMSC death was caspase-dependent. Further investigation demonstrated that leptin activated caspase-3 and caspase-9, but not caspase-8, and increased the cleavage of poly-(ADP-ribose) polymerase and cytochrome c release into cytosol. Leptin activated ERK, but not p38 and JNK, and up-regulated cPLA2 activity; the latter was abolished by pre-treatment of cells with the MEK inhibitor (PD98059 or U0126) or cPLA2 inhibitor (AACOCF3). PD98059, U0126, and AACOCF3 also diminished the leptin-induced cytochrome c release into cytosol, cell death, and caspase-3 activation. These data indicated that leptin induced hBMSC apoptosis via ERK/cPLA2/cytochrome c pathway with activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase. To our knowledge, this is the first study demonstrating the direct detrimental effect of leptin on bone cells.Leptin, the protein product encoded by obese gene, is a circulating hormone produced primarily by the adipose tissue and is a multifunctional hormone that plays important roles in body weight homeostasis, neuroendocrine function, fertility, immune function, and angiogenesis (1-3). The biological actions of leptin on target tissues are carried out through interaction with its specific receptor, Ob-R (4). A hallmark of Ob-R expression is the presence of several receptor variants (Ob-Ra through Ob-Rf) that are generated by alternative splicing; they share the same extracellular domain but differ in the length of the transmembrane/cytoplasmic coding regions (2). The long Ob-Rb subtype (Ob-R L ) appears as the functional, signal-transducing isoform, responsible for the action of leptin. The roles of the shorter Ob-R isoforms (Ob-R S ) remain to be characterized. Although leptin's precise sites of action are not known, its effect is thought largely mediated via hypothalamus. However, the wide expression of Ob-R L throughout the body suggests that leptin may also operate directly in peripheral tissues (5). There is now a significant amount of evidence implicating that leptin is active in the periphery (6).Recently, leptin has emerged as a key element in the regulation of bone mass. However, the mechanism by which leptin acts upon the bone remains unclear. Thomas et al. (7) reported that leptin enhanced the differentiation of hBMSC, 1 and Steppan et al. (8) reported that the femurs of leptindeficient ob/ob mice were shorter than those in the normal mice, and intraperitoneal injection of leptin significantly increas...

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Section: Leptin Receptors (Ob-r) Were Expressed In Hbmsc-usingmentioning

confidence: 83%

Leptin Induces Apoptosis via ERK/cPLA2/Cytochrome c Pathway in Human Bone Marrow Stromal Cells

Kim

Hong

Kim

et al. 2003

Journal of Biological Chemistry

115

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“…A complex transcriptional network regulates adipocyte differentiation (25,28,(73)(74)(75)(76)(77)(78)(79)(80)(81). Presumably any given corepressor variant associates with its specific nuclear receptor (and nonreceptor transcription factor) partners within this transcriptional network, each contributing to the regulation of different target genes, and each contributing to the many individual changes in the overall transcription program that result in adipocyte differentiation.…”

Section: Different Corepressor Variants Generate Different Transcriptmentioning

confidence: 99%

“…The 3T3-L1 pre-adipocyte cell line can be induced to differentiate into terminal adipocytes in culture (72). A series of nuclear receptors plays key roles in this differentiation phenomenon, including peroxisome-proliferator-activated receptors (PPARs), Rev-Erb, COUP-TFII, and thyroid hormone receptors (TRs) (25,28,(73)(74)(75)(76)(77)(78)(79)(80)(81). Agonists for certain of these receptors can accelerate the differentiation process (e.g.…”

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confidence: 99%

Alternative mRNA Splicing of Corepressors Generates Variants That Play Opposing Roles in Adipocyte Differentiation

Goodson

Mengeling

Jonas

et al. 2011

Journal of Biological Chemistry

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Background:The SMRT and NCoR corepressors play key biological roles in transcriptional repression. Results: Alternative mRNA splicing produces corepressor variants that can exert opposite effects on adipocyte differentiation. Conclusion: Corepressors are diversified by alternative mRNA splicing, allowing one locus to encode multiple proteins with distinct functions. Significance: Changes in alternative splicing may help drive the differentiation and customize the physiology of specific cell types.

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“…A role for gonadal steroid action in adipogenesis and adipocyte function has been realized for some time (473). This is evidenced by the well known gender differences that exist in the distribution of white adipose tissue in humans.…”

Section: Adipogenesismentioning

confidence: 99%

“…Supporting evidence for a functional relationship between the gonadal and adipogenesis systems is also provided by the direct correlation that exists between nutrition, body mass, and fat content with the onset of menarche in young females (475). In addition, white adipose tissue serves not only as an energy reservoir, but is also a site of steroid storage and metabolism that can supplement gonadal and adrenal synthesis and thereby influence the overall endocrine milieu (292,473).…”

Section: Adipogenesismentioning

confidence: 99%