Abstract
The neuroendocrine effects of leptin on metabolism hold promise to be translated into a complementary therapy to traditional insulin therapy for diabetes and obesity. However, injections of leptin can provoke inflammation. We tested the effects of leptin, produced in the physiological adipocyte location, on metabolism in mouse models of genetic and dietary obesity. We generated 3T3-L1 adipocytes constitutively secreting leptin and encapsulated them in a poly-L-lysine membrane, which protects the cells from immune rejection. Ob/ob mice (OB) were injected with capsules containing no cells (empty, OB[Emp]), adipocytes (OB[3T3]), or adipocytes overexpressing leptin (OB[Lep]) into both visceral fat depots. Leptin was found in the plasma of OB[Lep], but not OB[Emp] and OB[3T3] mice at the end of treatment (72 days). The OB[Lep] and OB[3T3] mice have transiently suppressed appetite and weight loss compared to OB[Emp]. Only OB[Lep] mice have greater brown fat mass, metabolic rate, and reduced resistin plasma levels compared to OB[Emp]. Glucose tolerance was markedly better in OB[Lep] vs. OB[Emp] and OB[3T3] mice as well as in wild type mice with high-fat diet-induced obesity and insulin resistance treated with encapsulated leptin-producing adipocytes. Our proof-of-principle study provides evidence of long-term improvement of glucose tolerance with encapsulated adipocytes producing leptin.
Highlights
Obesity affects 150 million people worldwide and is characterized as pandemic disease [1, 2]
A ratio of expressed Pref1 to Pparg was 98.4% lower in differentiated vs. non-differentiated 3T3-L1 cells (P
Studies have shown that the hypothalamic action of leptin on brown adipose tissues (BAT) and muscles can mediate lifesaving and antidiabetic actions on both insulin-resistant and insulin-deficient rodents [38]
Summary
Obesity affects 150 million people worldwide and is characterized as pandemic disease [1, 2]. In North America, European Union, China, and other countries, obesity is considered to be a PLOS ONE | DOI:10.1371/journal.pone.0153198. Therapeutic Effects of Lep Producing Adipocytes (CCTS), UL1RR025755 and NCI P30CA16058 (OSUCCC) from the National Center for Research Resources, funded by the Office of the Director (OD), National Institutes of Health and supported by the NIH Roadmap for Medical Research. The project described was supported by Award Number Grant UL1TR001070 from the National Center For Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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