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Division of
* Physiology and
Biochemistry, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland;
Clinique de réadaptation, SUVA Care, Sion, Switzerland;
Endocrinology of Energy Metabolism, Boston, Massachusetts, USA; and
|| Department of Biology, Faculty of Science, University of Fribourg, Fribourg, Switzerland
1Correspondence: Division of Physiology, Department of Medicine, University of Fribourg, Chemin du Musée 5, CH-1700 Fribourg, Switzerland. E-mail: abdul.dulloo{at}unifr.ch
SPECIFIC AIMS
An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a characteristic feature of body weight regulation after weight loss or growth retardation. It is viewed as the outcome of an "adipose-specific" suppression of thermogenesis, i.e., a feedback control system in which signals from the depleted adipose fat stores exert a suppressive effect on skeletal muscle thermogenesis to conserve energy in favor of catch-up fat. To elucidate the effector system of this adipose-specific suppression of thermogenesis, our specific aims were 1) to identify genes the altered expression of which in skeletal muscle during semistarvation would persist during refeeding in parallel to the suppressed thermogenesis that favors catch-up fat and 2) to validate the impact of altered expression of such gene(s) on skeletal muscle metabolism during both semistarvation and refeeding.
PRINCIPAL FINDINGS
1. Screening of candidate genes reveals stearoyl-coenzyme A desaturase 1
Using a rat model of semistarvation-refeeding in which catch-up fat results from suppressed thermogenesis per se (Fig. 1
), we first screened and validated, by quantitative RT-polymerase chain reaction (PCR), three sets of candidate genes for an expression profile of persistent up-regulation or down-regulation in skeletal muscle on day 7 of refeeding (i.e., at RF-7) after 2 wk of semistarvation (i.e., at RF-0). These three sets of candidate genes were as follows: 1) genes identified for showing this pattern of expression by the technique of differential display followed by microarray analysis, notably genes that code for muscle-specific proteins related to structure/contraction (myosins and collagen); 2) genes that are involved in calcium cycling (SERCA1, SERCA 2a, and sarcolipin) and that are known to be regulated by thyroid hormones; and 3) genes the deletion or overexpression of which, by gene manipulation technology in muscle cell systems or in generating transgenic mice, have been reported to result either in altered thermogenesis [PGC-1
mitofusin2, IL6, DGAT1, and stearoyl-coenzyme A desaturase 1 (SCD1)] or in an altered gene profile, which is consistent with ßbeta;-adrenergic control of thermogenesis (Nur77).
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In the overall analysis of these data, SCD1, an enzyme that catalyzes the synthesis of monounsaturated fatty acids (MUFAs) by introducing a double bond at the 
9 position of saturated fatty acids (SFA), was found to be the only translated gene that showed a pattern of expression that consistently correlated with a persistent suppression of thermogenesis directed at catch-up fat during refeeding after semistarvation.
2. Muscle-specificity in SCD1 gene up-regulation and hormonal regulation
The SCD1 transcript in skeletal muscle showed a robust elevation in mRNA levels of 2- to 4-fold relative to controls, both after 2 wk of semistarvation and after 1 wk of refeeding (Fig. 2
). These elevations in the SCD1 transcript are skeletal muscle specific, since they do not occur in liver or in adipose tissue. An examination of the pattern of changes in hormones that are capable of stimulating skeletal muscle thermogenesis and repressing SCD1, namely leptin, thyroid hormones, and possibly also catecholamines, revealed that at least two of them are lower than in controls during semistarvation (leptin, T3, and T4) or during subsequent refeeding (T3 and epinephrine) in parallel to the phase of suppressed thermogenesis that favors catch-up fat.
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3. Indices of increased muscle SCD1 activity
The functional relevance of these elevations in the SCD1 transcript to skeletal muscle lipid metabolism during semistarvation and refeeding is underlined by the results of subsequent analysis of microsomal and lipid fractions extracted from these muscles. These indicate parallel elevations in several indices of SCD1 enzyme activity both during semistarvation and refeeding, namely: 1) an increase in the 9 desaturase activity measured in the microsomal fractions; 2) an increase in the relative content of SCD1-derived MUFA, palmitoleolyl-coenzyme A (C16:1) and oleoyl-coenzyme A (C18:1), in several of the following lipid fractions: monoglycerides (MG), diglycerides (DG), triglycerides (TG), and phospholipids (PL); and 3) an increase in the 9 desaturation index that relates substrate and product in the reaction catalyzed by SCD1, namely palmitoyl-coenzyme A (C16:0) and stearoyl-coenzyme A (C18:0) as substrates, and palmitoleolyl-coenzyme A (C16:1) and oleoyl-coenzyme A (C18:1) as products. The 9 desaturation index is calculated as the ratio of C18:1/C18:0 or C16:1/C16:0 in each lipid fraction, using the quantitated values for palmitate (16:0), palmitoleate (16:1), stearate (18:0), and oleate (18:1) determined by gas chromatography/mass spectrometry.
These data reveal similarities, but also striking differences, in the changes in skeletal muscle lipid composition during semistarvation as opposed to those observed during refeeding. Whereas the elevations in the muscle 9 desaturation index and/or in the relative proportion of the SCD1-derived-MUFA were found in the MG and DG fractions both in response to semistarvation and to refeeding, they were only observed in the TG fraction in response to semistarvation and only in the PL fraction in response to refeeding.
CONCLUSIONS AND SIGNIFICANCE
The precise mechanisms by which these elevations in SCD1 activity and differential flux of SCD1-derived MUFA toward stored lipids (during semistarvation) or toward membrane lipids (during refeeding) might lead to suppressed thermogenesis in skeletal muscle are unknown. A common function of desaturases in organisms is to maintain the physical property of stored triglycerides and membrane lipids. One possible explanation therefore is that SCD1, by regulating the fatty acid composition of stored lipids and/or membrane phospholipids, induces modifications in lipid signaling molecules and/or membrane fatty acid composition that might alter the activities of multiple regulatory enzymes and proteins that are involved in the cellular effector system that mediates thermogenesis. Of particular relevance in this context are the findings that the enhanced thermogenesis in mice lacking SCD1 can be associated with increases in the activities of skeletal muscle phosphatidylinositol-3 kinase and AMP-activated protein kinase, two signaling pathways that have been shown to be required for hormonal stimulation of skeletal muscle thermogenesis through their actions in orchestrating substrate cycling between de novo lipogenesis and lipid oxidation. An alternative explanation is based on evidence that MUFA are much less potent than SFA as inhibitors of acetyl-coenzyme A carboxylase, the enzyme that catalyzes the synthesis of malonyl coenzyme A, the immediate precursor for de novo synthesis of fatty acids. The possibility therefore arises that SCD1 up-regulation, by increasing the conversion of de novo synthesized SFA to MUFA, would lead to diminished feedback inhibition of de novo synthesized fatty acids in the formation of their precursor substrate malonyl coenzyme A, which is also an inhibitor of mitochondrial CPT1 shuttle system that controls import and oxidation of fatty acids in mitochondria. Thus, as depicted in the biochemical model presented in Fig. 3
, by enhancing the conversion of the products of de novo lipogenesis to MUFA, an elevated SCD1 would divert de novo synthesized SFA and its MUFA products away from pathways of lipid ßbeta;-oxidation and effectively shut down this energy-dissipating substrate cycle, thereby leading to energy conservation. This model takes into account the differential effects of SCD1 up-regulation during semistarvation and refeeding, namely with the SCD1-derived MUFA being channeled, via the MG and DG intermediates of lipid metabolism, toward storage lipids (TG) during semistarvation, as opposed to being channeled toward membrane lipids (PL) during refeeding.
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In recent years, SCD1 has been proposed as a target for the treatment of obesity and the metabolic syndrome after the demonstrations that its disruption in mice leads to enhanced thermogenesis, which confers resistance to obesity and its comorbidities. Our findings here implicating a physiological role for skeletal muscle SCD1 up-regulation in the adaptive suppression of thermogenesis that regulates body fat stores therefore provide a physiological rationale for targeting skeletal muscle SCD1 or its lipid product moieties both in the management of obesity, as well as in counteracting the preferential catch-up fat phenotype that contributes to the pathophysiological consequences of rapid catch-up growth.
FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.06-5934fje
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2 wk. Skeletal muscle was harvested, namely at end of 2 wk semistarvation period, i.e., at onset of refeeding (RF-0) and after 1 wk of refeeding (RF-7). All values are means and SE. (n=6); **P < 0.01; ***P < 0.001.
