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. 2012 Nov;153(11):5622-8.
doi: 10.1210/en.2012-1462. Epub 2012 Sep 4.

Creation and preliminary characterization of a leptin knockout rat

Sergio Vaira  1 , Chang Yang, Aaron McCoy, Kelly Keys, Shurong Xue, Edward J Weinstein, Deborah V Novack, Xiaoxia Cui
Affiliations

Creation and preliminary characterization of a leptin knockout rat

Sergio Vaira et al. Endocrinology. 2012 Nov.

Abstract

Leptin, a cytokine-like hormone secreted mainly by adipocytes, regulates various pathways centered on food intake and energy expenditure, including insulin sensitivity, fertility, immune system, and bone metabolism. Here, using zinc finger nuclease technology, we created the first leptin knockout rat. Homozygous leptin null rats are obese with significantly higher serum cholesterol, triglyceride, and insulin levels than wild-type controls. Neither gender produced offspring despite of repeated attempts. The leptin knockout rats also have depressed immune system. In addition, examination by microcomputed tomography of the femurs of the leptin null rats shows a significant increase in both trabecular bone mineral density and bone volume of the femur compared with wild-type littermates. Our model should be useful for many different fields of studies, such as obesity, diabetes, and bone metabolism-related illnesses.

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Figures

Fig. 1.
Fig. 1.
LepΔ151/Δ151 rats are obese. A, Picture of a WT (Lep+/+) and a leptin-deficient rat (LepΔ151/Δ151) rat at 20 wk of age. B, Western blot analysis of total proteins extracted from white adipose tissues of WT and LepΔ151/Δ151 rats. Actin was used as loading control. The expected size for leptin is 16 kDa.
Fig. 2.
Fig. 2.
Leptin deficiency-induced obesity, glucose intolerance, and hyperinsulinemia. A, Body weight was measured over 18 wk for WT (Lep+/+, n = 4), heterozygous (Lep+/Δ151, n = 8), and homozygous (LepΔ151/Δ151, n = 45) males and WT (n = 2) and homozygous (n = 4) females. *, P < 0.01 vs. controls. B, Means ± se of daily food intake for Lep+/+ (n = 6) and LepΔ151/Δ151 (n = 6) measured over 3 wk of time. *, P < 0.05 vs. controls. C, Serum insulin levels in 4-wk-old WT and LepΔ151/Δ151 rats (n = 6 for each group). *, P < 0.05 vs. controls. D, Six- and 10-wk old WT and LepΔ151/Δ151 rats (n = 10 for each) were administrated with d-glucose, and serum glucose levels were determined at 0, 15, 30, 60, and 120 min after administration. *, P < 0.05 vs. controls.
Fig. 3.
Fig. 3.
LepΔ151/Δ151 rats have lower CD3 and CD4-positive T-cell population (A) and increased production of IFN-γ by CD4 and CD8-positive T cells (B). Whole-blood samples were stimulated with phorbol 12-myristate 13-acetate (PMA)/ionomycin and analyzed by flow cytometry for CD3, CD4, and CD8 cells subpopulations and for IFN-γ intracellular staining in CD4 and CD8 in LepΔ151/Δ151 (n = 11) and WT rats (n = 12). *, P < 0.05 vs. controls; **, P < 0.005.
Fig. 4.
Fig. 4.
Leptin disruption affected bone metabolism. A, Snapshots of μCT scan of trabecular bone of the femurs of 8-wk-old WT and LepΔ151/Δ151 rats. B, BV/TV (bone volume per tissue volume), Tb.N (trabecular number), Tb.Th (trabecular thickness), Tb.Sp. (trabecular spacing), BMD, and cortical area obtained from the μCT scan. C, Tibias from the same animals were fixed sectioned and TRAP (tartrate resistant acid phosphatase) stained for histomorphometric analysis. D, Osteoclast-related parameters, Oc.N (number of osteoclasts per bone surface), and Oc.S/BS (osteoclast surface per bone surface) were counted. E, BV/TV was also measured by histomorphometry on histological sections of the tibias. n = 8 for both WT and LepΔ151/Δ151 rats. *, P < 0.05 vs. controls.
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