A role for skeletal muscle stearoyl-CoA desaturase 1 in control of thermogenesis (original) (raw)
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Frontiers in Endocrinology, 2021
Refeeding after caloric restriction induces weight regain and a disproportionate recovering of fat mass rather than lean mass (catch-up fat) that, in humans, associates with higher risks to develop chronic dysmetabolism. Studies in a well-established rat model of semistarvation-refeeding have reported that catch-up fat associates with hyperinsulinemia, glucose redistribution from skeletal muscle to white adipose tissue and suppressed adaptive thermogenesis sustaining a high efficiency for fat deposition. The skeletal muscle of catch-up fat animals exhibits reduced insulin-stimulated glucose utilization, mitochondrial dysfunction, delayed in vivo contraction-relaxation kinetics, increased proportion of slow fibers and altered local thyroid hormone metabolism, with suggestions of a role for iodothyronine deiodinases. To obtain novel insights into the skeletal muscle response during catch-up fat in this rat model, the functional proteomes of tibialis anterior and soleus muscles, harves...
Journal of Applied Physiology, 2010
Stearoyl-CoA desaturase (SCD), a rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids, has recently been shown to be a critical control point in regulation of liver and skeletal muscle metabolism. Herein, we demonstrate that endurance training significantly increases both SCD1 mRNA and protein levels in the soleus muscle, whereas it does not affect SCD1 expression in the EDL muscle and liver. Desaturation index (18:1Δ9/18:0 ratio), an indirect indicator of SCD1 activity, was also significantly higher (3.6-fold) in soleus of trained rats compared with untrained animals. Consistent with greater SCD1 expression/activity, the contents of free fatty acids, diacylglycerol, and triglyceride were elevated in soleus of trained rats. However, training did not affect lipid concentration in EDL and liver. Additionally, endurance training activated the AMP-activated protein kinase pathway as well as increased peroxisome proliferator-activated receptor (PPAR)-δ and PPARα gene e...
International journal of biological sciences, 2008
Gene expression studies in humans and animals have shown that elevated stearoyl-CoA desaturase (SCD1) activity is associated with increased fat accumulation and monounsaturation of saturated fatty acids in skeletal muscle. However, results of the two reported association studies in humans are inconsistent. In the present study, we annotated the bovine SCD1 gene and identified 3 single nucleotide polymorphisms (SNPs) in its 3'untranslated region (UTR). Genotyping these SNPs on a Wagyu x Limousin reference population revealed that the SCD1 gene was significantly associated with six fat deposition and fatty acid composition traits in skeletal muscle, but not with subcutaneous fat depth and percent kidney-pelvic-heart fat. In particular, we confirmed that the high stearoyl-CoA desaturase activities/alleles were positively correlated with beef marbling score, amount of monounsaturated fatty acids and conjugated linoleic acid content, but negatively with amount of saturated fatty acid...
Journal of lipid …, 2004
Stearoyl-CoA desaturase (SCD) is a microsomal enzyme involved in the biosynthesis of oleate and palmitoleate. Mice with a targeted disruption of the SCD1 isoform (SCD1 ؊ / ؊ ) exhibit reduced adiposity and increased energy expenditure. To address whether the energy expenditure is attributable to increased thermogenesis, we investigated the effect of SCD1 deficiency on basal and coldinduced thermogenesis. SCD1 ؊ / ؊ mice have increased expression of uncoupling proteins in brown adipose tissue (BAT) relative to controls. The  3-adrenergic receptor (  3-AR) expression was increased and the phosphorylation of cAMP response element binding protein and the protein level of peroxisome proliferator-activated receptor-␥ coactivator-1 ␣ were increased in the SCD1 ؊ / ؊ mice. Both lipolysis and fatty acid oxidation were increased in the SCD1 ؊ / ؊ mice. When exposed to 4 Њ C, SCD1 ؊ / ؊ mice showed hypothermia, hypoglycemia, and depleted liver glycogen. High levels of dietary oleate partially compensated for the hypothermia and rescued plasma glucose and liver glycogen. These results suggest that SCD1 deficiency stimulates basal thermogenesis through the upregulation of the  3-ARmediated pathway and a subsequent increase in lipolysis and fatty acid oxidation in BAT. The hypothermia and hypoglycemia in cold-exposed SCD1 ؊ / ؊ mice and the compensatory recovery by oleate indicate an important role of SCD1 gene expression in thermoregulation. -Lee, S-H., A. Dobrzyn, P. Dobrzyn, S. M. Rahman, M. Miyazaki, and J. M. Ntambi. Lack of stearoyl-CoA desaturase 1 upregulates basal thermogenesis but causes hypothermia in a cold environment.
Diabetes, 2005
Catch-up growth, a risk factor for later obesity, type 2 diabetes, and cardiovascular diseases, is characterized by hyperinsulinemia and an accelerated rate for recovering fat mass, i.e., catch-up fat. To identify potential mechanisms in the link between hyperinsulinemia and catch-up fat during catch-up growth, we studied the in vivo action of insulin on glucose utilization in skeletal muscle and adipose tissue in a previously described rat model of weight recovery exhibiting catch-up fat caused by suppressed thermogenesis per se. To do this, we used euglycemic-hyperinsulinemic clamps associated with the labeled 2-deoxy-glucose technique. After 1 week of isocaloric refeeding, when body fat, circulating free fatty acids, or intramyocellular lipids in refed animals had not yet exceeded those of controls, insulin-stimulated glucose utilization in refed animals was lower in skeletal muscles (by 20 -43%) but higher in white adipose tissues (by two-to threefold). Furthermore, fatty acid synthase activity was higher in adipose tissues from refed animals than from fed controls. These results suggest that suppressed thermogenesis for the purpose of sparing glucose for catch-up fat, via the coordinated induction of skeletal muscle insulin resistance and adipose tissue insulin hyperresponsiveness, might be a central event in the link between catch-up growth, hyperinsulinemia and risks for later metabolic syndrome.
International Journal of Obesity, 2006
Mice lacking b-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epinephrine, show diminished thermogenesis and high susceptibility to obesity, whereas mice lacking stearoyl-CoA desaturase 1 (SCD1), which catalyzes the synthesis of monounsaturated fatty acids, show enhanced thermogenesis and high resistance to obesity. In testing whether b-adrenergic control of thermogenesis might be mediated via repression of the SCD1 gene, we found that in mice lacking b-adrenoceptors, the gene expression of SCD1 is elevated in liver, skeletal muscle and white adipose tissue. In none of these tissues/organs, however, could a link be found between increased sympathetic nervous system activity and diminished SCD1 gene expression when thermogenesis is increased in response to diet or cold, nor is the SCD1 transcript repressed by the administration of epinephrine. Taken together, these studies suggest that the elevated SCD1 transcript in tissues of mice lacking b-adrenoceptors is not a direct effect of blunted b-adrenergic signalling, and that b-adrenergic control of SCD1 repression is unlikely to be a primary effector mechanism in sympathoadrenal regulation of thermogenesis. Whether approaches that target both SCD1 and molecular effectors of thermogenesis under b-adrenergic control might be more effective than targeting SCD1 alone are potential avenues for future research in obesity management.
Skeletal Muscle Thermogenesis and Its Role in Whole Body Energy Metabolism
Obesity and diabetes has become a major epidemic across the globe. Controlling obesity has been a challenge since this would require either increased physical activity or reduced caloric intake; both are difficult to enforce. There has been renewed interest in exploiting pathways such as uncoupling protein 1 (UCP1)-mediated uncoupling in brown adipose tissue (BAT) and white adi-pose tissue to increase energy expenditure to control weight gain. However, relying on UCP1-based thermogenesis alone may not be sufficient to control obesity in humans. On the other hand, skeletal muscle is the largest organ and a major contributor to basal metabolic rate and increasing energy expenditure in muscle through nonshivering thermogenic mechanisms, which can substantially affect whole body metabolism and weight gain. In this review we will describe the role of Sarcolipin-mediated uncoupling of Sarcoplasmic Reticulum Calcium ATPase (SERCA) as a potential mechanism for increased energy expenditure both during cold and diet-induced thermogenesis.
International journal of obesity (2005), 2007
Mice lacking beta-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epinephrine, show diminished thermogenesis and high susceptibility to obesity, whereas mice lacking stearoyl-CoA desaturase 1 (SCD1), which catalyzes the synthesis of monounsaturated fatty acids, show enhanced thermogenesis and high resistance to obesity. In testing whether beta-adrenergic control of thermogenesis might be mediated via repression of the SCD1 gene, we found that in mice lacking beta-adrenoceptors, the gene expression of SCD1 is elevated in liver, skeletal muscle and white adipose tissue. In none of these tissues/organs, however, could a link be found between increased sympathetic nervous system activity and diminished SCD1 gene expression when thermogenesis is increased in response to diet or cold, nor is the SCD1 transcript repressed by the administration of epinephrine. Taken together, these studies suggest that the elevated SCD1 transcript in tissues of mice lacking beta-a...
Scientific Reports
A large number of studies have demonstrated significance of polyunsaturated fatty acids (PUFAs) for human health. However, many aspects on signals translating PUFA-sensing into body homeostasis have remained enigmatic. To shed light on PUFA physiology, we have generated a mouse line defective in mitochondrial dienoyl-CoA reductase (Decr), which is a key enzyme required for β-oxidation of PUFAs. Previously, we have shown that these mice, whose oxidation of saturated fatty acid is intact but breakdown of unsaturated fatty acids is blunted, develop severe hypoglycemia during metabolic stresses and fatal hypothermia upon acute cold challenge. In the current work, indirect calorimetry and thermography suggested that cold intolerance of Decr −/− mice is due to failure in maintaining appropriate heat production at least partly due to failure of brown adipose tissue (BAT) thermogenesis. Magnetic resonance imaging, electron microscopy, mass spectrometry and biochemical analysis showed attenuation in activation of lipolysis despite of functional NE-signaling and inappropriate expression of genes contributing to thermogenesis in iBAT when the Decr −/− mice were exposed to cold. We hypothesize that the failure in turning on BAT thermogenesis occurs due to accumulation of unsaturated long-chain fatty acids or their metabolites in Decr −/− mice BAT suppressing downstream propagation of NE-signaling. Core body temperature is crucial for survival of homeothermic animals in terms of keeping physical conditions amenable for maintenance of homeostasis and physiological activities. In addition to basal metabolism and mechanical work, mammals possess two other processes to enhance thermogenesis on demand; shivering thermogenesis in muscles and non-shivering thermogenesis in brown adipose tissue (BAT). BAT is a tissue capable of heat generation by uncoupling mitochondrial respiration from ATP generation through inner mitochondrial membrane residing uncoupling protein 1 (UCP1). UCP1 dissipates energy charge of transmembrane chemiosmostic force (H + gradient) as heat 1. Non-shivering thermogenesis in BAT is strictly controlled by the sympathetic nervous system, which conveys the stimulus of cold by releasing norepinephrine (NE) at adrenergic synapses in BAT. NE binds to β 3-adrenergic receptors, leading to an increase in intracellular cAMP concentration, followed by the initiation of intracellular signaling cascades required for thermogenesis; increased oxygen consumption, lipolysis and activation of gene expression. Free fatty acids released from white adipose tissue and taken up from circulation or intracellular lipid droplets are fueling thermogenesis and also acting as activators of UCP1. Polyunsaturated fatty acids (PUFAs) play multiple roles in maintenance of tissue homeostasis and human health. PUFAs and their metabolites regulate gene expression through various mechanisms including interactions with transcription factors, but also via causing changes in intracellular calcium level, membrane composition and eicosanoid production. In addition to regulation of gene expression, PUFAs are involved in post-translational regulation of protein abundance by regulating protein turnover and stability 2. Independent of either nutritional or endogenous metabolic origin of PUFAs in the body, their double bonds are mainly cis-bonds in either odd or even numbered