October 2, 2012

Encapsulated Fat-Metabolizing Cells Mitigate Obesity in Mice

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In a recent news article, we highlighted the urgency of the obesity epidemic and the role that endothelial nitric oxide synthase (eNOS) plays in the disease. In this article, we summarize recent research that explores the possibility of fighting obesity with implanted fat-metabolizing cells. For several decades, microcapsules fabricated from alginate-poly-L-lysine (APL) have been used to deliver engineered cells that produce bioactive therapeutic peptides, such as insulin, leptin, and growth factors, to specific locations in the body. Recently, researchers from the Department of Human Nutrition, Ohio State University, Columbus, led by Dr. Ouliana Ziouzenkova, demonstrated that such capsules can support the long term survival and functions of lipid-catabolizing cells and reduce visceral fat deposits in C57BL/6J (000664) female mice fed a high fat diet (Yang et al. 2012). These findings indicate that APL microcapsules could potentially be used to fight human metabolic disorders, including obesity.

Aldh1a1-/- mice are resistant to visceral obesity

Visceral fat plays an important role in obesity and associated diseases. It secretes cytokines that provoke insulin resistance and chronic inflammation and doubles the risk of cancer, cardiovascular disease, and premature death. Ziouzenkova and her colleagues found that female B6.129-Aldh1a1tm1Gdu/J (012247) mice, which are deficient for aldehyde dehydrogenase 1a1 (Aldh1a1) and vitamin A metabolites, are remarkably resistant to diet-induced visceral obesity (Ziouzenkova et al. 2007; Yasmeen et al. 2012). The reduced amounts of vitamin A metabolites in these mice increase metabolic rate, upregulate the expression of heat-generating genes, and increase body temperature. The Ziouzenkova team wondered if APL-encapsulated Aldh1a1-/- fibroblasts implanted in visceral fat could survive and mitigate obesity in high-fat-fed mice.

To clarify the effects of Aldh1a1 deficiency, Ziouzenkova and her colleagues fed Aldh1a1-/- and B6J mice a high-fat diet for 14 months. At the end of the 14 months, the Aldh1a1-/- mice weigh significantly less than wild-type B6J mice. The weight difference is due to a significantly lower amount of visceral and subcutaneous white adipose tissue in Aldh1a1-/- mice. At the end of the 14 months, the Aldh1a1-/- mice also exhibit moderately elevated thermogenesis.

Encapsulated Aldh1a1-/- fibroblasts lower lipid levels in vitro and in vivo

Ziouzenkova and her colleagues tested the ability of APL-encapsulated Aldh1a1-/- fibroblasts to lower lipid levels in vitro and in vivo. They found that these cells significantly lower triglyceride levels by nearly 62% in cultured NIH3T3-L1 adipocytes, indicating that they can lower the lipid content of surrounding cells. They then made B6J females obese by feeding them a high-fat diet for 90 days. They implanted the perigonadal visceral fat of these mice with either APL-encapsulated wild-type or Aldh1a1-/- fibroblasts, or mock capsules and fed them all a high-fat diet for 80 more days. Their key findings are summarized below:

  • The capsules stay in the visceral fat, and the fibroblasts contained therein do not proliferate to rupture the capsules
  • The fibroblasts (about 22,000/capsule) adhere in two-three layers to the inner capsule surfaces, which probably enables favorable small molecule exchange among transplanted and host cells
  • The microcapsules are surrounded by adipocytes (not by inflammatory cells or fibrosis), suggesting that they elicit relatively little immune response
  • Whereas mock- and wild-type fibroblast-implanted obese mice gain more weight when fed a high-fat diet for 80 more days, Aldh1a1-/- fibroblast-injected mice gain relatively little more
  • After feeding on the high-fat diet for 80 more days, Aldh1a1-/- fibroblast-implanted mice have a significantly lower (31%) visceral fat lipid content than wild-type fibroblast-implanted mice, suggesting that the encapsulated Aldh1a1-/- fibroblasts increase lipid metabolism in visceral fat
  • After feeding on the high-fat diet for 80 more days, Aldh1a1-/- fibroblast-implanted mice have significantly elevated UCP1 levels, which are inversely correlated with their visceral fat lipid content, indicating that UCP1 plays an important role in reducing the lipid content and dissipating energy in the visceral fat in these mice

In summary, Ziouzenkova and her colleagues demonstrated that APL-encapsulated Aldh1a1-/- fibroblasts can survive for long periods of time and mediate lipid catabolism when implanted in the visceral fat of obese B6J female mice. Implanting and removing the microcapsules is minimally invasive. The microcapsules elicit little if any immune response, their locations are easily detectable, and their contents readily analyzed. The findings by the Ziouzenkova team are proof of principle that microencapsulated Aldh1a1-/- fibroblasts could be used to mitigate human obesity.

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