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. 2002 Aug 6;99(16):10730-5.
doi: 10.1073/pnas.162349799. Epub 2002 Jul 29.

Adipose tissue mass can be regulated through the vasculature

Maria A Rupnick  1 , Dipak Panigrahy, Chen-Yu Zhang, Susan M Dallabrida, Bradford B Lowell, Robert Langer, M Judah Folkman
Affiliations

Adipose tissue mass can be regulated through the vasculature

Maria A Rupnick et al. Proc Natl Acad Sci U S A. .

Abstract

Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental system because of its remodeling capacity. Mice from different obesity models received anti-angiogenic agents. Treatment resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Marked vascular remodeling was evident in adipose tissue sections, which revealed decreased endothelial proliferation and increased apoptosis in treated mice compared with controls. Continuous treatment maintained mice near normal body weights for age without adverse effects. Metabolic adaptations in food intake, metabolic rate, and energy substrate utilization were associated with anti-angiogenic weight loss. We conclude that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature.

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Figures

Fig 1.
Fig 1.
Body weight responses to angiogenesis inhibitors. We treated 8-week-old ob/ob mice with various doses of TNP-470 (A) or angiostatin (B) for 21 days (n = 4 per group). (C) Responses of ob/ob mice treated with various angiogenesis inhibitors (hatched bars) for 7 d were compared with those of the corresponding vehicles (solid bars) and leptin (n = 3 per group). (D) Twelve-week-old mice from various obesity models were treated with vehicle (solid bars) or TNP-470 (hatched bars) for 7 days (n = 3 per group). These included agouti mice C57BL/6J-Ay (Ay), fat mice C57BLKS-Cpefat/J (Cpefat), ob/ob mice C57BL/6J-Lepob, and wild-type C57BL/6J mice fed a high-fat diet consisting of 40% fat by calorie (n = 3 per group).
Fig 2.
Fig 2.
Continuous and intermittent treatment of ob/ob mice with TNP-470. (A) ob/ob mice were treated with vehicle (n = 4) or TNP-470 (10 mg/kg/day; n = 6) starting at 8 weeks of age for 138 days, or at 6 months of age for 65 days. For comparison, the graph includes the growth curve of wild-type, age-matched C57BL/6 mice (n = 5). (B) Mice were treated with TNP-470 (10 mg/kg/day; n = 15) until they reduced to the weight of age-matched C57BL/6 mice. We then discontinued treatment, and the mice were permitted to regain before treatment was restarted. We cycled treatment four times. (C) Photographs show a representative mouse from each group on 173 days (bottom of cycle 4). Except for superficial scarring, daily TNP-470 treatment was well tolerated.
Fig 3.
Fig 3.
Body compositions of ob/ob mice treated with TNP-470 or leptin. Nine-week-old female ob/ob mice were treated with TNP-470 (5 mg/kg/day) or leptin (150 μg/kg/day) for 7 days to achieve similar weight reduction (n = 4 per group). Control ob/ob mice received vehicle. (A) Body weight curves. (B) Daily food intakes. (C) Fat mass (black bars) and lean body mass (gray bars) components of body composition were measured using dual-energy x-ray absorptiometry.
Fig 4.
Fig 4.
Adipose tissue endothelial cell proliferation and apoptosis in ob/ob mice. (A) Endothelial cell proliferation and apoptosis were evaluated in epididymal adipose tissue sections from ob/ob mice following 7 days of treatment with vehicle, TNP-470, or leptin. We identified endothelial cells (red) by using vWF. We used fluorescein (green) with BrdUrd to identify proliferating cells (Left) or with the TUNEL assay to identify apoptotic cells (Right). Cells stained with both markers appear yellow. Adipose tissue from control ob/ob mice contained proliferating endothelial cells (yellow, top left), occasional proliferating nonendothelial cells (green), and few apoptotic endothelial cells (yellow, top right). In contrast, adipose tissue from TNP-470- and leptin-treated mice contained numerous apoptotic endothelial cells (yellow, middle and bottom right). (Bar = 25 μm.) (B) Median percents of endothelial cell proliferation and apoptosis were quantified for 30 high power fields per section (n = 5 per group). We used a box and whisker plot to illustrate the median and range of the measurements.
Fig 5.
Fig 5.
Appetite of ob/ob mice treated with angiogenesis inhibitors. Eight-week-old ob/ob mice (n = 4 per group) with free access to chow were treated with (A) TNP-470 (10 mg/kg/day), (B) angiostatin (50 mg/kg/12 h), or (C) endostatin (50 mg/kg per 12 h). We fed the amount consumed per day by each treated mouse to a paired mouse in a second, untreated group (n = 4). We measured body weights of treated, paired-fed, and control mice daily.
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References

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