DOI: 10.1111/exd.12335 www.wileyonlinelibrary.com/journal/EXD
Commentary from the Editorial Board
Leptin controls hair follicle cycling Reiko Watabe, Takashi Yamaguchi, Rieko Kabashima-Kubo, Manabu Yoshioka, Daisuke Nishio and Motonobu Nakamura Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan Correspondence: Motonobu Nakamura, Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan, Tel.: +81-93-691-7445, Fax:+81-93-691-0907, e-mail: [email protected] Abstract: Leptin is a cytokine well known for its ability to control body weight and energy metabolism. Several lines of evidence have recently revealed that leptin also plays an important role in wound healing and immune modulation in skin. Sumikawa et al. Exp Dermatol 2014 evaluated the effect of leptin on hair follicle cycling using mutant and wild-type mice. They report that leptin is produced in dermal papilla cells in hair follicles and that leptin receptor–deficient db/db mice show an abnormality in hair follicle cycling. Moreover, leptin injection induced the transition into the
growth stage of the hair cycle (anagen). On this basis, it now deserves exploration whether leptin-mediated signalling is a key stimulus for anagen induction and whether this may be targeted to manage human hair disorders with defect in the control of hair follicle cycling.
Leptin is a 16-kD hormone or cytokine predominantly synthesized and secreted by adipocytes (1). Leptin was named after its main biological effect (from the Greek word leptos = lean). Subcutaneous and visceral fat is the primary source of this protein encoded by the obese (ob) gene (2). In concert with other adipokine signals released by adipocytes, leptin is regarded as one of the main endogenous regulators of body weight and energy metabolism. Leptin secretion is positively correlated with body mass and therefore obesity is accompanied with high circulating leptin levels (1). Leptin binds to a leptin receptor (ObR), which comprises of six isoforms, ObRa to f, encoded by diabetes genes. ObR mutations generate the diabetes db/db mouse models (3). The ObRs are members of the interleukin-6 (IL-6) receptor family of the class I cytokine receptor superfamily. ObR is most closely related to gp130, the signal transducing membrane protein of the IL-6 signalling complex. One of the most important intra-cellular signal transduction molecules of the leptin is signal transducer and activator of transcription 3 (STAT3) (4). After the binding of leptin with ObRs, STAT3 is phosphorylated and activated via ObRJAK2-STAT3 signalling pathway (Fig. 1). Leptin acts as a metabolic neurohormone on the hypothalamus, which expresses ObR abundantly, to suppress food intake and increase energy expenditure. Recently, leptin has been reported to play a key role also in the skin (1). Leptin and its receptors are expressed by both fibroblasts and keratinocytes (5–7). In the interfollicular epidermis, leptin immunoreactivity is most prominently observed in the basal and suprabasal layer. This leptin synthesis and secretion are strongly upregulated after skin injury, and leptindeficient mice showed severely impaired and delayed wound healing (5). Leptin induces keratinocyte proliferation and epithelization, fibroblast proliferation and collagen synthesis, as well as angiogenesis, resulting in accelerated wound repair and skin regeneration.
Leptin can also enhance antimicrobial defenses in human skin by stimulating innate immunity by the induction of antimicrobial peptide, human-defensin 2 (8). Besides wound healing and immune modulation, in this issue of Experimental Dermatology, Sumikawa et al. elegantly showed that leptin also controls hair cycling in skin (9). The hair follicle (HF) displays unique, lifelong, cyclic transformations between stages of rapid growth of hair shafts (anagen), apoptosis-driven regression (catagen) and relative resting (telogen) controlled by an ectodermal–mesenchymal interaction (10). Every phase of the hair cycle is characterized by defined, tightly regulated programs of tissue proliferation, differentiation and apoptosis that are governed by the local balance of numerous growth-stimulatory and growthinhibitory signals (11–15). A lot of mouse mutants deficient in soluble factors, receptors and transcription factors show abnormalities in hair cycling (12,14). In a recent issue of Experimental Dermatology, Japanese group uncovered a role of another important molecule, leptin, in the regulation of hair cycling (9). Immunohistochemical study revealed that leptin immunoreactivity was detected in dermal papilla cells in catagen, telogen and early anagen, as previously reported in human dermal papilla cells (9,16). Dermal papilla cells are mesenchyme-derived and indispensable for the control of hair cycling (1). Real-time PCR analysis demonstrated that leptin mRNA expression in dermal papilla cells was enhanced by hypoxia due to CoCl2, fitting into the data of its high expression between catagen and early anagen. Western blot analysis revealed that phosphorylation of STAT3 took place in kerationocytes after the addition of leptin in the culture medium. In leptin receptor–deficient db/db mice, anagen transition was significantly retarded compared with wild-type mice. Moreover, injection of leptin into the shaved dorsal skin of wild-type mice induced the hair growth around the injected area 20 days later, while the mock-treated control showed no change.
228
Key words: dermal papilla – hair cycle – leptin – STAT3
Accepted for publication 30 January 2014
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 228–229
Commentary from the Editorial Board
Leptin
Leptin receptor
STAT3
Weight control
Hair cycle regulation
Wound healing
Immune modulation
Figure 1. Leptin controls weight, hair cycling, wound healing and immune systems through leptin receptors (ObR) and STAT3.
the duration of anagen becomes shortened due to the production of dihydrotestosterone from testosterone in dermal papilla cells, and in alopecia areata, an autoaggressive inflammatory cell infiltrate forces anagen hair follicles into catagen; vice versa, hirsutism typically is associated with prolonged anagen (10,15). Therefore, it now deserves exploration whether leptin-mediated signalling is a key stimulus for anagen induction and whether leptin receptor agonists or antagonists can be employed to manage human hair disorders with defect in the control of hair follicle cycling. Further evaluation of the efficacy and safety of this hair growth-modulatory strategy in humans as well as appropriate vehicles [ideally for topical, hair follicle-targeting application (17)] are sensible next steps towards the clinical application of leptin.
Author Contributions RW, TY, RK, MY, DN and MN wrote the manuscript.
These data suggested that leptin is an anagen inducer. Several hair disorders are characterized by a defect in the proper control of hair follicle cycling (14). For example, in androgenetic alopecia,
References
1 Poeggeler B, Schulz C, Pappolla M A et al. Exp Dermatol 2010: 19: 12–18. 2 Halaas J L, Gajiwala K S, Maffei M et al. Science 1995: 269: 543–546. 3 Tartaglia L A, Dembski M, Weng X et al. Cell 1995: 83: 1263–1271. 4 Bates S H, Stearns W H, Dundon T A et al. Nature 2003: 421: 856–859. 5 Murad A, Nath A K, Cha S T et al. FASEB J 2003: 17: 1895–1897. 6 Frank S, Stallmeyer B, Kmpfer H et al. J Clin Invest 2000: 106: 501–509.
Conflict of interests The authors declare no conflicting interest.
7 Glasow A, Kiess W, Anderegg U et al. J Clin Endocrinol Metab 2001: 86: 4472–4479. 8 Kanda N, Watanabe S. Endocrinology 2008: 149: 5189–5198. 9 Sumikawa Y, Inui S, Nakajima T et al. Exp Dermatol 2014: 23: 27–32. 10 Paus R, Cotsarelis G. N Engl J Med 1999: 341: 491–497. 11 Botchkarev V A, Botchkareva N V, Roth W et al. Nat Cell Biol 1999: 1: 158–164. 12 Nakamura M, Sundberg J P, Paus R. Exp Dermatol 2001: 10: 369–390.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 228–229
13 Nakamura M, Matuzuk M M, Gerstmayer B et al. FASEB J 2003: 17: 497–499. 14 Nakamura M, Schneider M R, Schmidt-Ullrich R et al. J Dermatol Sci 2013: 69: 6–29. 15 McElwee K J, Gilhar A, Tobin D J et al. Exp Dermatol 2013: 22: 609–626. 16 Iguchi M, Aiba S, Yoshimo Y et al. J Invest Dermatol 2001: 17: 1349–1356. 17 Patzelt A, Lademann J. Expert Opin Drug Deliv 2013: 10: 787–797.
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Commentary from the Editorial Board
Leptin controls hair follicle cycling Reiko Watabe, Takashi Yamaguchi, Rieko Kabashima-Kubo, Manabu Yoshioka, Daisuke Nishio and Motonobu Nakamura Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan Correspondence: Motonobu Nakamura, Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan, Tel.: +81-93-691-7445, Fax:+81-93-691-0907, e-mail: [email protected] Abstract: Leptin is a cytokine well known for its ability to control body weight and energy metabolism. Several lines of evidence have recently revealed that leptin also plays an important role in wound healing and immune modulation in skin. Sumikawa et al. Exp Dermatol 2014 evaluated the effect of leptin on hair follicle cycling using mutant and wild-type mice. They report that leptin is produced in dermal papilla cells in hair follicles and that leptin receptor–deficient db/db mice show an abnormality in hair follicle cycling. Moreover, leptin injection induced the transition into the
growth stage of the hair cycle (anagen). On this basis, it now deserves exploration whether leptin-mediated signalling is a key stimulus for anagen induction and whether this may be targeted to manage human hair disorders with defect in the control of hair follicle cycling.
Leptin is a 16-kD hormone or cytokine predominantly synthesized and secreted by adipocytes (1). Leptin was named after its main biological effect (from the Greek word leptos = lean). Subcutaneous and visceral fat is the primary source of this protein encoded by the obese (ob) gene (2). In concert with other adipokine signals released by adipocytes, leptin is regarded as one of the main endogenous regulators of body weight and energy metabolism. Leptin secretion is positively correlated with body mass and therefore obesity is accompanied with high circulating leptin levels (1). Leptin binds to a leptin receptor (ObR), which comprises of six isoforms, ObRa to f, encoded by diabetes genes. ObR mutations generate the diabetes db/db mouse models (3). The ObRs are members of the interleukin-6 (IL-6) receptor family of the class I cytokine receptor superfamily. ObR is most closely related to gp130, the signal transducing membrane protein of the IL-6 signalling complex. One of the most important intra-cellular signal transduction molecules of the leptin is signal transducer and activator of transcription 3 (STAT3) (4). After the binding of leptin with ObRs, STAT3 is phosphorylated and activated via ObRJAK2-STAT3 signalling pathway (Fig. 1). Leptin acts as a metabolic neurohormone on the hypothalamus, which expresses ObR abundantly, to suppress food intake and increase energy expenditure. Recently, leptin has been reported to play a key role also in the skin (1). Leptin and its receptors are expressed by both fibroblasts and keratinocytes (5–7). In the interfollicular epidermis, leptin immunoreactivity is most prominently observed in the basal and suprabasal layer. This leptin synthesis and secretion are strongly upregulated after skin injury, and leptindeficient mice showed severely impaired and delayed wound healing (5). Leptin induces keratinocyte proliferation and epithelization, fibroblast proliferation and collagen synthesis, as well as angiogenesis, resulting in accelerated wound repair and skin regeneration.
Leptin can also enhance antimicrobial defenses in human skin by stimulating innate immunity by the induction of antimicrobial peptide, human-defensin 2 (8). Besides wound healing and immune modulation, in this issue of Experimental Dermatology, Sumikawa et al. elegantly showed that leptin also controls hair cycling in skin (9). The hair follicle (HF) displays unique, lifelong, cyclic transformations between stages of rapid growth of hair shafts (anagen), apoptosis-driven regression (catagen) and relative resting (telogen) controlled by an ectodermal–mesenchymal interaction (10). Every phase of the hair cycle is characterized by defined, tightly regulated programs of tissue proliferation, differentiation and apoptosis that are governed by the local balance of numerous growth-stimulatory and growthinhibitory signals (11–15). A lot of mouse mutants deficient in soluble factors, receptors and transcription factors show abnormalities in hair cycling (12,14). In a recent issue of Experimental Dermatology, Japanese group uncovered a role of another important molecule, leptin, in the regulation of hair cycling (9). Immunohistochemical study revealed that leptin immunoreactivity was detected in dermal papilla cells in catagen, telogen and early anagen, as previously reported in human dermal papilla cells (9,16). Dermal papilla cells are mesenchyme-derived and indispensable for the control of hair cycling (1). Real-time PCR analysis demonstrated that leptin mRNA expression in dermal papilla cells was enhanced by hypoxia due to CoCl2, fitting into the data of its high expression between catagen and early anagen. Western blot analysis revealed that phosphorylation of STAT3 took place in kerationocytes after the addition of leptin in the culture medium. In leptin receptor–deficient db/db mice, anagen transition was significantly retarded compared with wild-type mice. Moreover, injection of leptin into the shaved dorsal skin of wild-type mice induced the hair growth around the injected area 20 days later, while the mock-treated control showed no change.
228
Key words: dermal papilla – hair cycle – leptin – STAT3
Accepted for publication 30 January 2014
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 228–229
Commentary from the Editorial Board
Leptin
Leptin receptor
STAT3
Weight control
Hair cycle regulation
Wound healing
Immune modulation
Figure 1. Leptin controls weight, hair cycling, wound healing and immune systems through leptin receptors (ObR) and STAT3.
the duration of anagen becomes shortened due to the production of dihydrotestosterone from testosterone in dermal papilla cells, and in alopecia areata, an autoaggressive inflammatory cell infiltrate forces anagen hair follicles into catagen; vice versa, hirsutism typically is associated with prolonged anagen (10,15). Therefore, it now deserves exploration whether leptin-mediated signalling is a key stimulus for anagen induction and whether leptin receptor agonists or antagonists can be employed to manage human hair disorders with defect in the control of hair follicle cycling. Further evaluation of the efficacy and safety of this hair growth-modulatory strategy in humans as well as appropriate vehicles [ideally for topical, hair follicle-targeting application (17)] are sensible next steps towards the clinical application of leptin.
Author Contributions RW, TY, RK, MY, DN and MN wrote the manuscript.
These data suggested that leptin is an anagen inducer. Several hair disorders are characterized by a defect in the proper control of hair follicle cycling (14). For example, in androgenetic alopecia,
References
1 Poeggeler B, Schulz C, Pappolla M A et al. Exp Dermatol 2010: 19: 12–18. 2 Halaas J L, Gajiwala K S, Maffei M et al. Science 1995: 269: 543–546. 3 Tartaglia L A, Dembski M, Weng X et al. Cell 1995: 83: 1263–1271. 4 Bates S H, Stearns W H, Dundon T A et al. Nature 2003: 421: 856–859. 5 Murad A, Nath A K, Cha S T et al. FASEB J 2003: 17: 1895–1897. 6 Frank S, Stallmeyer B, Kmpfer H et al. J Clin Invest 2000: 106: 501–509.
Conflict of interests The authors declare no conflicting interest.
7 Glasow A, Kiess W, Anderegg U et al. J Clin Endocrinol Metab 2001: 86: 4472–4479. 8 Kanda N, Watanabe S. Endocrinology 2008: 149: 5189–5198. 9 Sumikawa Y, Inui S, Nakajima T et al. Exp Dermatol 2014: 23: 27–32. 10 Paus R, Cotsarelis G. N Engl J Med 1999: 341: 491–497. 11 Botchkarev V A, Botchkareva N V, Roth W et al. Nat Cell Biol 1999: 1: 158–164. 12 Nakamura M, Sundberg J P, Paus R. Exp Dermatol 2001: 10: 369–390.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 228–229
13 Nakamura M, Matuzuk M M, Gerstmayer B et al. FASEB J 2003: 17: 497–499. 14 Nakamura M, Schneider M R, Schmidt-Ullrich R et al. J Dermatol Sci 2013: 69: 6–29. 15 McElwee K J, Gilhar A, Tobin D J et al. Exp Dermatol 2013: 22: 609–626. 16 Iguchi M, Aiba S, Yoshimo Y et al. J Invest Dermatol 2001: 17: 1349–1356. 17 Patzelt A, Lademann J. Expert Opin Drug Deliv 2013: 10: 787–797.
229
