Acyl CoA:diacylglycerol acyltransferase (DGAT) is a ubiquitously expressed enzyme that catalyzes the final reaction in the major pathways of triglyceride synthesis. Mice lacking DGAT1 (Dgat–/–) demonstrate significant changes in lipid metabolism in several tissues, including the skin. Here we report the effects of DGAT1 deficiency on fur and sebaceous glands. Adult Dgat–/– mice had dry fur and hair loss, which were associated with atrophic sebaceous glands and fur lipid abnormalities. As a result, Dgat–/– mice had impaired water repulsion and defective thermoregulation after water immersion. These phenotypes were mostly absent in Dgat–/– mice with leptin deficiency, indicating an unexpected role for leptin in modulating the skin phenotype. Our findings indicate that DGAT1 plays an important role in normal fur and sebaceous gland physiology and provide evidence that leptin modulates these processes in the skin.
Hubert C. Chen, Steven J. Smith, Bryan Tow, Peter M. Elias, Robert V. Farese Jr.
Submitter: Paul Trayhurn | p.trayhurn@liverpool.ac.uk
Department of Medicine, University of Liverpool, Liverpool, U.K.
Published February 11, 2002
"Leptin modulates the effects of acyl CoA:diacylglycerol acyltransferase deficiency on murine fur and sebaceous glands"
Sir:
We were most interested in the article by Chen et al in the January 2002, No. 2, issue of JCI. In this study, the authors report that mice lacking DGAT1 (Dgat-/-) exhibit deficiencies in their fur and sebaceous glands, as well as having other abnormalities of the skin. They also demonstrate an intriguing, unrelated, finding indicating that there is an interaction between leptin and DGAT1 in skin. It is concluded that the skin is a site of action of leptin, and this adds to the wide range of functions with which this hormone has been implicated.
We have earlier shown that both the leptin and leptin receptor (Ob-R and Ob-Rb) genes are expressed in the skin of fetal mice, and particularly in the hair follicles near where the sebaceous glands are located (1, 2). The presence of leptin and leptin receptor protein, as well as mRNA, was identified in our work and another study also found leptin receptor expression in the dermis of the skin of both newborn and adult mice (3). At the time, the role of leptin in the skin was unclear, either for the hormone apparently synthesised locally or that produced by adipose tissue. Expression of both leptin and its receptor were identified at the earliest point in the mouse fetus (13.5 days) at which skin can be differentiated from the aggregation of cells which are the fore-runners of hair follicles (2).
Chen et al also report that the effects of leptin on sebaceous glands can be mediated through the hypothalamus, as well as there being a direct response to the peripheral administration of the hormone. The presence of locally produced leptin, as we have documented (1, 2), suggests that there is a paracrine effect in hair follicles and this may be more important than an endocrine effect through adipose tissue-derived hormone. The high expression of leptin receptors in the hair follicles of fetal mice suggests that the skin is a particular and early site of leptin action. Indeed, the strong expression of leptin receptors in hair follicles contrasts with the liver, adrenals and pancreas of fetal mice where leptin receptor mRNA was undetectable by in situ hybridisation - despite receptor expression occurring in these organs in adult rodents. Overall, it is clear that there is considerable value in examining the developing fetus in order to gain insight into the sites of actions and physiological roles of leptin.
References
1. Hoggard, N., Hunter, L., Duncan, J.S., Williams, L.M., Trayhurn, P., and Mercer, J.G. 1997. Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta. Proc. Natl. Acad. Sci. USA 94:11073-11078.
2. Hoggard, N., Hunter, L., Lea, R.G., Trayhurn, P., and Mercer, J.G. 2000. Ontogeny of the expression of leptin and its receptor in the murine fetus and placenta. Br. J. Nutr. 83:317-26.
3. Chen, S.C., Kochan, J.P., Campfield, L.A., Burn, P., and Smeyne, R.J. 1999. Splice variants of the OB receptor gene are differentially expressed in brain and peripheral tissues of mice. J Recept. Signal Transduct. Res. 19: 245-266.
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