Targeted Overexpression of Leptin to Keratinocytes in Transgenic Mice Results in Lack of Skin Phenotype but Induction of Early Leptin Resistance

Targeted Overexpression of Leptin to Keratinocytes in Transgenic Mice Results in Lack of Skin Phenotype but Induction of Early Leptin Resistance

The epidermis has a great potential as a bioreactor to produce proteins with systemic action. However, the consequences of ectopic epidermal protein overexpression need to be carefully addressed to avoid both local and systemic adverse effects. Thus, the long-term effects of leptin on skin physiolog...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) Vol. 146; no. 10; pp. 4167 - 4176
Main Authors: Rico, Laura, Del Rio, Marcela, Bravo, Ana, Ramirez, Angel, Jorcano, José L, Page, M. Angustias, Larcher, Fernando
Format: Journal Article
Language:English
Published: Bethesda, MD Endocrine Society 01-10-2005
Subjects:
Adipose Tissue - cytology
Animals
Animals, Newborn
Biological and medical sciences
Body Weight
Cell Differentiation
Drug Resistance - genetics
Energy Intake
Epidermis - cytology
Epidermis - physiology
Fundamental and applied biological sciences. Psychology
Keratin-15
Keratin-5
Keratinocytes - physiology
Keratins - genetics
Leptin - blood
Leptin - genetics
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Transgenic
Skin - cytology
Vertebrates: endocrinology
Wound Healing
Induction
Rodentia
Transgenic animal
Gene overexpression
Adipokine
Resistance
Vertebrata
Phenotype
Mammalia
Mouse
Leptin
Keratinocyte
Skin
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Summary:The epidermis has a great potential as a bioreactor to produce proteins with systemic action. However, the consequences of ectopic epidermal protein overexpression need to be carefully addressed to avoid both local and systemic adverse effects. Thus, the long-term effects of leptin on skin physiology have not been studied, and the metabolic consequences of sustained keratinocyte-derived leptin overexpression are unknown. Herein we describe that very high serum leptin levels can be achieved from a cutaneous source in transgenic mice in which leptin cDNA overexpression was driven by the keratin K5 gene regulatory sequences. Histopathological analysis including the study of skin differentiation and proliferation markers in these transgenic mice revealed that keratinocyte-derived leptin overexpression appears not to have any impact on cutaneous homeostasis. Although young K5-leptin transgenic mice showed remarkable thinness and high glucose metabolism as shown in other leptin transgenic mouse models, a marked leptin insensitivity become apparent as early as 3–4 months of age as demonstrated by increased weight gain and insulin resistance development. Other signs of leptin/insulin resistance included increased bone mass, organomegaly, and wound healing impairment. In addition, to provide evidence for the lack of untoward effects of leptin on epidermis, this transgenic mouse helps us to establish the safe ranges of keratinocyte-derived leptin overexpression and may be useful as a model to study leptin resistance.
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content type line 23
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2005-0156