TY - JOUR
T1 - cAMP-dependent Signaling Regulates the Adipogenic Effect of n-6 Polyunsaturated Fatty Acids
AU - Madsen, Lise
AU - Pedersen, Lone Møller
AU - Liaset, Bjørn
AU - Ma, Tao
AU - Petersen, Rasmus Koefoed
AU - van den Berg, Sjoerd
AU - Pan, Jie
AU - Müller-Decker, Karin
AU - Dülsner, Erik D
AU - Kleemann, Robert
AU - Kooistra, Teake
AU - Døskeland, Stein Ove
AU - Kristiansen, Karsten
PY - 2008
Y1 - 2008
N2 - The effect of n-6 polyunsaturated fatty acids (n-6 PUFAs) on adipogenesis and obesity is controversial as fundamentally opposing results both in vivo and in vitro have been reported. Using in vitro cell culture models we show that the adipogenic action of the n-6 PUFA arachidonic acid was dependent on the intracellular levels of cAMP. In conditions with baseline intracellular levels of cAMP, n-6 PUFAs acted pro-adipogenic, whereas n-6 PUFAs acted anti-adipogenic when the intracellular levels of cAMP were elevated. The anti-adipogenic action of n-6 PUFAs was dependent on a PKA-mediated induction of cyclooxygenase (COX) expression and activity. In vivo the intracellular levels of cAMP are modulated in response to dietary intake of different classes of macronutrients. Accordingly, we show that n-6 PUFAs were pro-adipogenic when combined with a high carbohydrate diet, but non-adipogenic when combined with a high protein diet in mice. The high protein diet increased the glucagon/insulin ratio, leading to elevated cAMP-dependent signaling and induction of COX-mediated prostaglandin synthesis. Mice fed the high protein diet had a markedly lower feed efficiency than mice fed the high carbohydrate diet. Yet, oxygen consumption and apparent heat production were similar. Mice on a high protein diet had increased hepatic expression of PGC-1a and genes involved in energy demanding processes like urea synthesis and gluconeogenesis. We conclude that cAMP signaling is pivotal in regulating the adipogenic effect of n-6 PUFAs, and that diet-induced differences in cAMP levels can explain the ability of n-6 PUFAs to either enhance or counteract adipogenesis and obesity.
AB - The effect of n-6 polyunsaturated fatty acids (n-6 PUFAs) on adipogenesis and obesity is controversial as fundamentally opposing results both in vivo and in vitro have been reported. Using in vitro cell culture models we show that the adipogenic action of the n-6 PUFA arachidonic acid was dependent on the intracellular levels of cAMP. In conditions with baseline intracellular levels of cAMP, n-6 PUFAs acted pro-adipogenic, whereas n-6 PUFAs acted anti-adipogenic when the intracellular levels of cAMP were elevated. The anti-adipogenic action of n-6 PUFAs was dependent on a PKA-mediated induction of cyclooxygenase (COX) expression and activity. In vivo the intracellular levels of cAMP are modulated in response to dietary intake of different classes of macronutrients. Accordingly, we show that n-6 PUFAs were pro-adipogenic when combined with a high carbohydrate diet, but non-adipogenic when combined with a high protein diet in mice. The high protein diet increased the glucagon/insulin ratio, leading to elevated cAMP-dependent signaling and induction of COX-mediated prostaglandin synthesis. Mice fed the high protein diet had a markedly lower feed efficiency than mice fed the high carbohydrate diet. Yet, oxygen consumption and apparent heat production were similar. Mice on a high protein diet had increased hepatic expression of PGC-1a and genes involved in energy demanding processes like urea synthesis and gluconeogenesis. We conclude that cAMP signaling is pivotal in regulating the adipogenic effect of n-6 PUFAs, and that diet-induced differences in cAMP levels can explain the ability of n-6 PUFAs to either enhance or counteract adipogenesis and obesity.
U2 - 10.1074/jbc.M707775200
DO - 10.1074/jbc.M707775200
M3 - Journal article
C2 - 18070879
SN - 0021-9258
VL - 283
SP - 7196
EP - 7205
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 11
ER -
