Lipolytic Action of Corticotropin on Rat Adipose Tissue In Vitro12

White, Jay D.; Engel, Frank L.

doi:10.1172/jci103748

Cited by 234 publications

(43 citation statements)

References 13 publications

(19 reference statements)

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“…This response peaked on day 4 and was completely absent in untreated cells on day 5 (5u). Therefore, these data are consistent with previous studies, which have shown the ACTH response to be differentiationdependent (7,8).…”

Section: Resultssupporting

confidence: 93%

“…However, a pharmacological analysis showed that the actions of ACTH were mediated solely through the MC2-R in this cell line (2). ACTH exerts a potent lipolytic effect on the murine adipocyte via the cAMP pathway (7,8) and has more recently been shown to suppress the expression and secretion of the appetite regulating hormone leptin in differentiated 3T3-L1 cells (9). MC2-R expression may therefore be important in providing feedback between the hypothalamo-pituitary-adrenal axis and peripheral leptin production by adipose tissue.…”

mentioning

confidence: 87%

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A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

Noon

Clark

King

2004

Journal of Biological Chemistry

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Adrenocorticotropic hormone can stimulate lipolysis and suppress leptin expression in murine adipocytes. These effects are mediated via the melanocortin 2 receptor (MC2-R), which is expressed when 3T3-L1 cells are induced to undergo adipogenesis. In this study, we have characterized the mc2-r promoter in the murine adipocyte, one of the few extra-adrenal sites of expression and a cell type that lacks steroidogenic factor 1 (SF-1), a transcription factor that is required for mc2-r expression in adrenal cells. Transcriptional regulation of the mc2-r in the absence of SF-1 was investigated by 5 deletion analysis of the murine mc2-r promoter in both undifferentiated and differentiated 3T3-L1 cells. The results revealed the presence of a 59-base pair regulatory region within the promoter containing an adipocytespecific enhancer. The ability of this region to confer enhanced activity in the adipocyte was mapped to a peroxisome proliferator-response element (PPRE)-like sequence that bound to peroxisome proliferator-activated receptor ␥ (PPAR␥) and its heterodimeric partner retinoid X receptor ␣ (RXR␣) in adipocyte nuclear extracts. Co-transfection of PPAR␥2/RXR␣ with the pMC2-R(؊112/؉105)GL3 reporter resulted in transcriptional activation in preadipocytes, and this response required an intact PPRE. Mutation of the PPRE to prevent PPAR␥/RXR␣ binding resulted in a complete abrogation of the pMC2-R(؊112/؉105)GL3 reporter activity in day 3 differentiated 3T3-L1 cells, demonstrating a key role played by this site in regulating MC2-R expression in the murine adipocyte. These data highlight a novel mechanism for mc2-r transcription, which may have significance in both adrenal and extra-adrenal sites of expression.The melanocortin 2 receptor (MC2-R) 1,2 is a seven-transmembrane G-protein coupled receptor best known for its role in the adrenal cortex where it couples the actions of adrenocorticotropic hormone (ACTH) to steroidogenesis and increased glucocorticoid output (1). Although the key role of MC2-R in the hypothalamo-pituitary-adrenal axis has been the focus of the majority of publications to date, it is also expressed in a number of extra-adrenal sites including the murine adipocyte, fetal testis, human skin, and sympathetic ganglia (2-5).Early studies using the murine 3T3-L1 cell line, a widely used model of adipogenesis, demonstrated the appearance of high affinity ACTH binding sites following treatment of growth-arrested cells with a mixture of adipogenic agents including insulin, dexamethasone, and 3-isobutyl-1-methyl-xanthine (6). Subsequent characterization of the melanocortin receptors expressed by 3T3-L1 adipocytes revealed the presence of both the MC2 and MC5-R. However, a pharmacological analysis showed that the actions of ACTH were mediated solely through the MC2-R in this cell line (2). ACTH exerts a potent lipolytic effect on the murine adipocyte via the cAMP pathway (7, 8) and has more recently been shown to suppress the expression and secretion of the appetite regulating hormone leptin in differentiated 3...

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Section: Resultssupporting

confidence: 93%

mentioning

confidence: 87%

A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

Noon

Clark

King

2004

Journal of Biological Chemistry

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“…Recently, it was demonstrated that mouse adipocytes express high levels of melanocortin 2 (MC2) receptor (28). The ligand for the MC2 receptor is adrenocorticotropic hormone (ACTH), a potent lipolytic stimulant in rat adipocytes (29,30). Therefore, agouti antagonism of ACTH binding to its adipocyte receptor may lead to an inhibition of ACTH-mediated lipolysis.…”

Section: Discussionmentioning

confidence: 99%

Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity

Mynatt

Miltenberger

Klebig

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The agouti gene product is a secreted protein that acts in a paracrine manner to regulate coat color in mammals. Several dominant mutations at the agouti locus in mice cause the ectopic, ubiquitous expression of agouti, resulting in a condition similar to adult-onset obesity and non-insulin-dependent diabetes mellitus. The human agouti protein is 85% homologous to mouse agouti; however, unlike the mouse agouti gene, human agouti is normally expressed in adipose tissue. To address whether expression of agouti in human adipose tissue is physiologically relevant, transgenic mice were generated that express agouti in adipose tissue. Similar to most humans, these mice do not become obese or diabetic. However, we found that daily insulin injections significantly increased weight gain in the transgenic lines expressing agouti in adipose tissue, but not in nontransgenic mice. These results suggest that insulin triggers the onset of obesity and that agouti expression in adipose tissue potentiates this effect. Accordingly, the investigation of agouti's role in obesity and non-insulin-dependent diabetes mellitus in mice holds significant promise for understanding the pathophysiology of human obesity.

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“…The mobilization of free fatty acids as metabolic fuels is elicited by lipolytic hormones, such as adrenaline (Gordon and Cherkes, 1958), ACTH (White and Engel, 1958), growth hormone (Raben and Hollenberg, 1958), and glucagon (Vaughn et al, 1964). The mechanism of action of these hormones on lipolysis has mainly been explained by the second messenger concept of Sutherland and his co-worker (Sutherland and Butcher, 1965).…”

Section: Discussionmentioning

confidence: 99%

Effects of adrenergic blocking agents on lipolysis and adenyl cyclase activity induced by vasoactive intestinal polypeptide (VIP).

et al. 1978

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Lipolytic Action of Corticotropin on Rat Adipose Tissue In Vitro12

Cited by 234 publications

References 13 publications

A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity

Effects of adrenergic blocking agents on lipolysis and adenyl cyclase activity induced by vasoactive intestinal polypeptide (VIP).

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