Impaired noradrenaline-induced lipolysis in white fat of aP2-Ucp1 transgenic mice is associated with changes in G-protein levels

Abstract

In vitro experiments suggest that stimulation of lipolysis by catecholamines in adipocytes depends on the energy status of these cells. We tested whether mitochondrial uncoupling proteins (UCPs) that control the efficiency of ATP production could affect lipolysis and noradrenaline signalling in white fat in vivo. The lipolytic effect of noradrenaline was lowered by ectopic UCP1 in white adipocytes of aP2-Ucp1 transgenic mice, overexpressing the UCP1 gene from the aP2 gene promoter, reflecting the magnitude of UCP1 expression, the impaired stimulation of cAMP levels by noradrenaline and the reduction of the ATP/ADP ratio in different fat depots. Thus only subcutaneous but not epididymal fat was affected. UCP1 also down-regulated the expression of hormone-sensitive lipase and lowered its activity, and altered the expression of trimeric G-proteins in adipocytes. The adipose tissue content of the stimulatory G-protein alpha subunit was increased while that of the inhibitory G-protein alpha subunits decreased in response to UCP1 expression. Our results support the idea that the energy status of cells, and the ATP/ADP ratio in particular, modulates the lipolytic effects of noradrenaline in adipose tissue in vivo. They also demonstrate changes at the G-protein level that tend to overcome the reduction of lipolysis when ATP level in adipocytes is low. Therefore, respiratory uncoupling may exert a broad effect on hormonal signalling in adipocytes.

Mouse Betaine-Homocysteine S-Methyltransferase Deficiency Reduces Body Fat via Increasing Energy Expenditure and Impairing Lipid Synthesis and Enhancing Glucose Oxidation in White Adipose Tissue

“…These differences in GWAT and IWAT may explain why effects in Bhmt Ϫ/Ϫ IWAT are more pronounced. Other investigators also report metabolic differences between GWAT and IWAT (39).…”

Role of energy charge and AMP-activated protein kinase in adipocytes in the control of body fat stores

“…33 All the effects of transgenic UCP1 on the biochemical properties of white fat in the aP2-Ucp1 mice seem to be in agreement with the activation of AMPK (see above). Indeed, it was observed that UCP1-induced decrease in the ATP/ADP ratio in the subcutaneous white fat of transgenic mice 25 was also associated with a reduced ATP/ AMP ratio, increased activity of AMPK, and enhanced oxidation of FA. 27 Less dramatic changes were also observed in the gonadal fat of these mice.…”

“…In parallel, UCP1 transgene caused a downregulation of hormone-sensitive lipase (HSL), lowered its activity, and altered the expression of G-proteins in adipocytes. 25 The LPL activity in gonadal fat was higher in the transgenic compared to control mice, especially when the animals were fed a high-fat diet. 21 In agreement, we found that plasma TG levels were significantly lower in transgenic mice.…”

“…The latter was observed only in the subcutaneous but not gonadal fat depot of transgenic mice. 25 Moreover, decreased FA synthesis was accompanied by a downregulation of acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), 26 and peroxisome proliferator-activated receptor g (PPARg) 27 in the white fat. Transgenic UCP1 lowered FA synthesis by means of respiratory uncoupling, as confirmed by experiments in vitro.…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…That mitochondrial uncoupling in WAT could reduce obesity was found in 1995 by Kopecky et al (1995) using aP2-Ucp1 transgenic mice and explored systematically later on (Kopecky et al 1996a, b;Stefl et al 1998;Baumruk et al 1999;Rossmeisl et al 2000Rossmeisl et al , 2002Rossmeisl et al , 2005Flachs et al 2002;Matejkova et al 2004). In these mice, the fatspecific aP2 promoter was used to drive expression of UCP1 from the whole genomic DNA sequence, resulting in enhanced expression of UCP1 in both WAT and BAT of mice with C57BL/6 J background.…”