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Endocrinology Vol. 146, No. 10 4165-4166
Copyright © 2005 by The Endocrine Society

Bioengineering Obesity: The Skinny on Leptin Delivery

Matthew Hickey

Departments of Health and Exercise Science, Food Science and Human Nutrition, and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523

Address all correspondence and requests for reprints to: Matthew Hickey, Ph.D., B215 A Moby Complex, Campus Delivery 1582, Colorado State University, Fort Collins, Colorado 80523. E-mail: matthew.hickey{at}colostate.edu.

Achieving stable local or systemic delivery of therapeutic transgenes, delivered from readily accessible and safe target tissues, remains a major challenge in gene therapy (1, 2, 3). Presently the most common tissue targets include skeletal muscle, liver, and the lung (1, 2, 3). The lung presents significant advantages due to the substantial epithelial-blood capillary network and relative accessibility (4). However, both the liver and lung represent critical-for-life organs, and there are significant (but not insurmountable) concerns about the safety of gene therapy in these target organs (1, 2, 3). Skeletal muscle has been suggested to be a less-than-ideal target because it is not a tissue that is physiologically designed for secretion (1), although there is emerging evidence that skeletal muscle is far more active as a secretory organ than previously thought (5, 6).

Novel target organs for gene therapy include salivary glands (1) and keratinocytes (7, 8, 9), both of which can serve as platforms for systemic delivery of transgenic proteins for clinical purposes. The present issue of Endocrinology contains a report by Rico et al. (10) that describes the use of transgenic keratinocytes overexpressing leptin to achieve systemic bioactivity. Rico et al. establish the effective delivery of leptin to the systemic circulation (with systemic leptin reaching ~80–110 ng/ml) and a temporary blunting of weight gain, compared with wild-type controls. Importantly, the skin phenotype was unaffected by the transgene, suggesting that this is a well-tolerated route of delivery for leptin. The authors report blunted weight gain and energy intake, significantly reduced adipose tissue mass, and increased glucose tolerance in transgenic animals vs. wild-type controls for approximately 3 months. However, the transgenic animals (males in particular) displayed rapid catch-up growth such that by 6 months, the transgenic animals weighed approximately 14% more than controls. After 6 months, the transient leptin-induced changes in energy intake and glucose metabolism relative to the wild-type controls were also lost, despite sustained elevations in systemic leptin. The loss of leptin action in the transgenic animals is clear evidence of the induction of leptin resistance. To their credit, the authors have carefully phenotyped both the target organ for gene delivery (skin) and the organism proper in the transgenic animals to characterize the effects of sustained cutaneous delivery of leptin. Whereas the skin phenotype was unaffected by the transgene, the induction of leptin resistance (attended by insulin resistance) resulted in organomegaly, impaired wound healing, and increased bone mass in transgenic animals.

This report is noteworthy for a number of reasons. First, it highlights the importance of continuing to explore alternative tissue targets to address the challenges of gene therapy in general. Second, with respect to therapeutic applications of leptin, it presents a model wherein the challenges posed by the induction of leptin resistance may be able to be more systematically addressed. Research on the therapeutic use of bioengineered skin for treatment of systemic conditions has an interesting history; a classic early study by Morgan et al. (11) provided evidence that GH could be detected in the media from cultured keratinocytes expressing the GH gene. This group also established that epidermal grafts from athymic mice also expressed GH (11). Subsequent studies have documented measurable systemic levels of GH, erythropoietin, factor IX, cytokines, and even apolipoprotein E (cf. Refs.7, 8, 9 and 12). The latter is noteworthy in that apolipoprotein E is a 299-amino acid protein with a molecular mass of approximately 34 kDa, which clearly shows that relatively large proteins can have systemic access from bioengineered skin. The systemic delivery of biologically active proteins (either directly into sc circulation or via lymphatic circulation) is an exciting development, with great therapeutic promise. The potential application of bioengineered skin to serve as a bioreactor for delivery of therapeutic doses of proteins/hormones is substantial (see Fig. 1Go). The accessibility of skin to therapeutic control in terms of regulated gene delivery is also noteworthy; Cao et al. (8, 9) reported on the development of a gene switch system whereby a cutaneous transgene is regulated by a topical cream that contains an inducer. These authors documented increased systemic GH and evidence of GH biological activity (weight gain) in transgenic mice treated with a topical inducer. In addition to serving as a potential platform for drug delivery and gene therapy, bioengineered cells have also been studied as modifiable metabolic sinks that would serve as adjunct detoxification sites with therapeutic use for inborn errors of metabolism (13, 14, 15).



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  		FIG. 1. Potential therapeutic applications of bioengineered skin. Transgenic keratinocytes can be grafted onto a host and serve as a platform for the therapeutic delivery of local or systemically acting proteins (either via direct delivery into the cutaneous circulation or via the lymph system). In addition, bioengineered skin cells may also act as metabolic sinks, clearing metabolic by-products that have accumulated in the circulation, such as methylmalonyl CoA in methylmalonyl CoA mutase deficiency, ornithine in ornithine-{delta} amino transferase deficiency, or phenylalanine in phenylketonuria. The potential applications for both gene delivery and metabolic sink therapy are far broader than the limited examples presented herein. ApoE, Apolipoprotein E; EPO, erythropoietin; MCM, methylmalonyl coenzyme A mutase; OAT, ornithine delta aminotransferase; PKU, phenylketonuria. [Adapted from Refs.2 , 3 , and 6 7 8 9 10 11 12 13 14 .]

 
Rico et al. (10) also highlight a specific challenge associated with the therapeutic administration of leptin, namely the induction of leptin resistance. Because the overwhelming majority of obese humans have high systemic leptin levels without the attendant reductions in energy intake or increases in energy expenditure that follow leptin administration in experimental settings, it has been suggested that obesity is a state of leptin resistance (16, 17). Considerable work has been directed toward developing a clear understanding of the nature of leptin resistance over the past 10 yr. The two model targets of leptin resistance that have received the most attention include the well-documented saturable transport of leptin across the blood-brain barrier and the potential for postreceptor signaling defects (16). With respect to the former, there is evidence of a reduced cerebrospinal fluid to plasma leptin ratio in obesity (i.e. the high plasma leptin in obesity does not lead to a correspondingly high central leptin, which may blunt leptin action). Considerable debate remains about the biological significance of this proposed mechanism because functional regions of the brain involved in leptin action (most notably the arcuate nucleus) may not be wholly protected by the blood-brain barrier (16). In terms of postreceptor signaling defects, there is now convincing evidence of impaired signaling in the hypothalamus of obese rodents (16). Leptin resistance is manifested by attenuated janus kinase-signal transducer and activator of transcription signaling and an increase signal transducer and activator of transcription-3 and via the insulin receptor substrate-phosphatidylinositol 3-kinase pathway (16). Importantly, there is emerging evidence of postreceptor signaling defects in leptin-resistant states in peripheral tissues as well (18).

The creative integration of bioengineering, gene therapy, and physiology may ultimately allow for the development of sustainable treatments for both common disorders such as obesity and rare inborn errors of metabolism. The studies of Rico et al. (10) have highlighted both the promise and challenges associated with engineering such treatments. To the extent that similar studies continue to provide useful information for both the basic scientist and clinician, the field will move closer to the goal of optimal therapeutics.

Received July 7, 2005.

Accepted for publication July 7, 2005.


   References
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  2. Voutetakis A, Kok MR, Zheng C, Bossis I, Wang J, Cotrim AP, Marracino N, Goldsmith CM, Chiorini JA, Loh YP, Neiman LK, Baum BJ 2004 Reengineered salivary glands are stable endogenous bioreactors for systemic gene therapeutics. Proc Nat Acad Sci USA. 101:3053–3058
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  4. Englehardt JF 2002 The lung as a metabolic factory for gene therapy. J Clin Invest. 110:429–432
  5. Tomas E, Kelly M, Xiang X, Tsao TS, Keller C, Keller P, Luo Z, Lodish H, Saha AK, Unger R, Ruderman NB 2004 Metabolic and hormonal interactions between muscle and adipose tissue. Proc Nutr Soc. 63:381–385
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  10. Rico L, Del Rio M, Bravo A, Ramirez A, Jorcano JL, Page MA, Larcher F 2005 Targeted overexpression of leptin to keratinocytes in transgenic mice results in lack of skin phenotype but induction of early leptin resistance. Endocrinology 146:4167–4176[Abstract/Free Full Text]
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