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Johanna Samulin disputerte 25. september 2008
Ane Gro Siri SkjelfjordAn increase in the occurrence of obesity and related diseases in developed countries has created a need for a better understanding of the regulation of adipose tissue development.
Adipocytes play a central role in the regulation of energy balance, both as a reservoir, storing and releasing fuel, and as endocrine cells, secreting factors that regulate the whole body energy homeostasis. An increase in the occurrence of obesity and related diseases in developed countries has created a need for a better understanding of the regulation of adipose tissue development. Adipogenesis involves the proliferation of preadipocytes and their differentiation into mature adipocytes. The differentiation process itself is characterised by changes in cell morphology and is regulated by complex molecular events controlled by signalling from hormones, growth factors and components of the extracellular matrix. Interestingly, preadipocytes from different fat depots have distinct adipogenic potential and mature adipocytes exhibit differences in metabolic activity. Moreover, visceral abdominal but not subcutaneous obesity is related to an increased risk for developing type 2 diabetes and atherosclerosis. Regulatory pathways and increased expression of transcription factors and lipogenic genes during adipogenesis are well documented in the commonly used mouse 3T3-¬LI preadipocyte line. Rodents have distinct brown adipose tissue depots throughout life, whereas both pigs and humans are essentially deficient in brown adipose tissue depots at adult age. Because brown adipose tissue is highly catabolic these species differences may affect metabolic regulation. Pigs have a very similar morphology and metabolic regulation to humans, and have potential to be a good biomedical model for human metabolic disorders. Despite an increased interest in pigs as a model for obesity, little is known about porcine adipogenesis and few studies have investigated the temporal expression patterns of lipid metabolism associated genes in proliferating and differentiating porcine preadipocytes.
In this thesis we present gene expression profiles during porcine adipogenesis and investigate differences in differentiating preadipocytes of visceral and subcutaneous origin. Porcine visceral preadipocytes have not been previously studied and our novel findings demonstrate a more rapid cell proliferation and lipid accumulation in subcutaneous than in visceral porcine preadipocytes. Interestingly, depot specific differences in the expression patterns of catalase (CAT), carnitine palmitoyltransferase lB (CPT1B) and adipocyte-type fatty acid binding protein (FABP4) were observed. Depot specific differences in the function and metabolism of mature porcine adipocytes are plausible and are in accordance with observations in mice and humans.
Temporal gene expression analysis of subcutaneous porcine preadipocytes indicates that porcine adipogenesis closely resemble murine adipogenesis. Transcripts involved in fatty acid and triacylglycerol synthesis were highly increased during porcine adipogenesis. Moreover, a high degree of desaturation and elongation was measured in differentiated adipocytes and the expression of elongation and desaturation genes were induced during preadipocyte differentiation. Porcine preadipocytes also displayed an increase in the expression of peroxisome proliferator-activated receptor alpha and gamma (PPARA, PPARG), and sterol regulatory element-binding protein l (SREBP-1C) during differentiation. Surprisingly, peroxisome proliferator-activated receptor beta (PPARB) was not regulated throughout porcine adipogenesis, even though a role of PPARB has been described in early murine adipogenesis. A decreased expression of delta-like l (DLK1), commonly used as a marker of preadipocyte stages, was also observed during porcine adipogenesis. The novel porcine DLK1A and DLK1C as well as earlier described porcine DLK1B and DLK1C2 splice variants were expressed in adipose tissue and differentiating preadipocytes. Interestingly, the shorter DLK1C and DLK1C2 alternatively spliced transcripts were strikingly downregulated during porcine adipogenesis, in contrast to the longer DLK1 variants in mice. Interestingly, even though the fatty acid oxidation activity was low in differentiated adipocytes, the expression of genes involved in lipolysis and fatty acid oxidation was upregulated during porcine adipogenesis. Differentiating porcine preadipocytes also had a higher relative increase in the expression of muscle/heart-type fatty acid binding protein (FABP3) than FABP4. These findings demonstrate that even though the gene expression patterns during porcine adipogenesis appear highly similar to that in mice and humans, some differences in the regulation of preadipocyte proliferation and the fatty acid transport and oxidation in differentiating preadipocytes likely exist between species.
Key words / ISI database key words: Adipocyte differentiation; differentiation; porcine; depot origin; gene expression; subcutaneous; visceral; stromal-vascular cells; elongation; desaturation; fatty acid oxidation; lipid metabolism; pig; proliferaton; adipogenesis; fatty acid binding proteins; peroxisome proliferator-activated response; alternative splicing; delta-like 1.
Address pr. July 2009: Rikshospitalet, Institutt for kirurgisk forskning, 0027 Oslo, Norway
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Oppdatert: 01.07.09
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