The prolonged survival of fibroblasts with forced lipid catabolism in visceral fat following encapsulation in alginate-poly-l-lysine

Abstract

Although alginate-poly-L-lysine (APL) encapsulation of cells producing bioactive peptides has been widely tested, it is unknown whether APL supports lasting catabolic functions of encapsulated cells in adipose tissue, which are required for obesity reduction. We tested functions of APL-encapsulated fibroblasts isolated from wild-type (WT) and aldehyde dehydrogenase 1a1 knockout mice (KO), which resist obesity on a high-fat (HF) diet, have a higher metabolic rate, and express increased levels of thermogenic uncoupling protein-1 (Ucp1) in their deleterious visceral fat depots compared to WT mice. To enable in vivo detection and quantification, fibroblasts were stably transfected with green-fluorescent protein. WT- or KO-containing microcapsules were injected into two visceral depots of WT mice fed an HF diet. Eighty days after transplantation, microcapsules were located in vivo using magnetic resonance imaging. KO microcapsules prevented weight gain in obese WT mice compared to a mock- and WT capsule-injected groups on an HF diet. The weight loss in KO-treated mice corresponded to lipid reduction and induction of thermogenesis in the injected visceral fat. The non-treated subcutaneous fat was not altered. Our data suggest that the APL polymer supports long-term catabolic functions of genetically-modified fibroblasts, which can be potentially used for depot-specific obesity treatment.

Cell encapsulation: technical and clinical advances

“…Materials can also be designed in ways that enable realtime imaging to confirm implant location and function of cells encapsulated into those materials. The precise location of the implanted cell-loaded capsules may be determined by traditional imaging modalities, including magnetic resonance imaging (MRI) [21][22][23][24] or ultrasound [25]. For example, microcapsules can be coated with selfassembled gold nanoparticles, which enable them to be monitored by X-ray micro-CT scanners [26,27].…”

Sarcolipin Is a Key Determinant of the Basal Metabolic Rate, and Its Overexpression Enhances Energy Expenditure and Resistance against Diet-induced Obesity

“…Whole-body Oxygen Consumption and Physical Activity Measurement-Oxygen consumption (VO 2 ), CO 2 production (VCO 2 ), respiratory exchange ratio (RER, VCO 2 /VO 2 ), and heat production (energy expenditure) were measured simultaneously using an Oxymax comprehensive laboratory animal monitoring system (Columbus Instruments, Columbus, OH) (15,16). These parameters were measured individually in a resting state at the housing temperature (29°C Ϯ 1.0°C) with ad libitum food and water.…”

Enzymatic intracrine regulation of white adipose tissue

“…In WAT, thermogenesis can be induced by either sympathetic nerve stimulation, prolonged cold exposure [21], or consumption of high-fat and spicy diets [22]. Induction of thermogenesis in WAT can change energy homeostasis and effectively decrease obesity and insulin resistance [9, 23, 24]. Notably, the increased proportion of thermogenic to lipogenic adipocytes in abdominal fat can decrease lipid accumulation in this deleterious depot [23].…”

“…Induction of thermogenesis in WAT can change energy homeostasis and effectively decrease obesity and insulin resistance [9, 23, 24]. Notably, the increased proportion of thermogenic to lipogenic adipocytes in abdominal fat can decrease lipid accumulation in this deleterious depot [23]. Although thermogenesis in WAT offers a unique therapeutic opportunity to decrease abdominal fat, the current methods of inducing thermogenesis in WAT are not suitable for clinical application.…”

“…We found that resistance to high-fat diet was more pronounced in Aldh1a1 -/- female than Aldh1a1 -/- male mice as a result of the high rate of lipolysis and thermogenesis in the visceral fat depot, where ALDH1A1 was a single enzyme responsible for RA generation [9]. Although responses in Aldh1a1 -/- mice were a sum of systemic, tissue, and cell-based effects, thermogenesis was regulated largely autonomously, because immortalized Aldh1a1 -/- fibroblasts maintained thermogenic characteristics in cell culture [23]. This study suggested that Aldh1a1 -mediated intracrine signaling is sufficient to suppress thermogenesis in adipocytes.…”