Paton CM, Ntambi JM. Biochemical and physiological function of stearoylCoA desaturase.

Stearoyl-CoA desaturase-1 (SCD1) catalyzes the synthesis of monounsaturated fatty acids and is an important regulator of whole body energy homeostasis. Severe cutaneous changes in mice globally deficient in SCD1 also indicate a role for SCD1 in maintaining skin lipids. We have generated mice with a skinspecific deletion of SCD1 (SKO) and report here that SKO mice display marked sebaceous gland hypoplasia and depletion of sebaceous lipids. In addition, SKO mice have significantly increased energy expenditure and are protected from high fat diet-induced obesity, thereby recapitulating the hypermetabolic phenotype of global SCD1 deficiency. Genes of fat oxidation, lipolysis, and thermogenesis, including uncoupling proteins and peroxisome proliferator-activated receptor-␥ co-activator-1␣, are up-regulated in peripheral tissues of SKO mice. However, unlike mice globally deficient in SCD1, SKO mice have an intact hepatic lipogenic response to acute high carbohydrate feeding. Despite increased basal thermogenesis, SKO mice display severe cold intolerance because of rapid depletion of fuel substrates, including hepatic glycogen, to maintain core body temperature. These data collectively indicate that SKO mice have increased cold perception because of loss of insulating factors in the skin. This results in up-regulation of thermogenic processes for temperature maintenance at the expense of fuel economy, illustrating cross-talk between the skin and peripheral tissues in maintaining energy homeostasis.Obesity is a multifactorial disease stemming from a combination of genetic, dietary, and lifestyle factors and the interaction between these components (1-3). The microsomal enzyme, stearoyl-CoA desaturase-1 (SCD1), 3 is a critical control point in the development of metabolic diseases, including obesity and insulin resistance. SCD1 catalyzes the conversion of saturated fatty acids, such as palmitate (16:0) and stearate (18: 0), into their ⌬-9 monounsaturated products, palmitoleate (16:1 n-7) and oleate (18:1 n-9), respectively. Mice lacking the SCD1 enzyme because of a global deletion of the Scd1 gene (GKO) are lean and protected from diet-induced and leptin deficiency-induced obesity. These mice have a marked increase in energy expenditure and almost complete protection from high fat diet-induced weight gain and glucose intolerance (4 -10). Because SCD1 is expressed in multiple tissues, including liver, brown and white adipose tissue, skeletal muscle, and skin, it has been difficult to determine the relative contributions of these tissues to the dramatically altered metabolic phenotypes of GKO mice. Studies using antisense oligonucleotide-mediated approaches to knock down Scd1 expression have reported protection from diet-induced weight gain and hepatic insulin resistance upon hepatic SCD1 inhibition (11-13). However, whereas the liver is a major target of these antisense oligonucleotides, they have also been reported to affect expression of target genes in adipose tissue (13,14) and possibly other organs (15). Using Cre re...

In its role as an endothelial cell proliferation and migration factor, vascular endothelial growth factor (VEGF) can affect peripheral circulation and therefore impact maximal oxygen consumption (Vo2 max). Because of the role of VEGF, and because variation in the VEGF gene has the ability to alter VEGF gene expression and VEGF protein level, we hypothesized that VEGF gene polymorphisms are related to VEGF gene expression in human myoblasts and Vo2 max before and after aerobic exercise training. We analyzed the effects of the VEGF -2578/-1154/-634 promoter region haplotype on VEGF gene expression by using a luciferase reporter assay in cultured human myoblasts and found that the AAG and CGC haplotypes resulted in significantly higher hypoxia-stimulated VEGF gene expression than the AGG and CGG haplotypes. Consistent with these results, we found that individuals with at least one copy of the AAG or CGC haplotype had higher Vo2 max before and after aerobic exercise training than did subjects with only the AGG and/or CGG haplotype. In conclusion, we found that VEGF -2578/-1154/-634 haplotype impacts VEGF gene expression in human myoblasts and is associated with Vo2 max. These results have potential implications for aerobic exercise training and may prove relevant in the study of pathological conditions that can be affected by angiogenesis, such as coronary artery disease and peripheral artery disease.

We previously reported that mice with skin-specific deletion of stearoyl-CoA desaturase-1 (Scd1) recapitulated the skin phenotype and hypermetabolism observed in mice with a whole-body deletion of Scd1. In this study, we first performed a diet-induced obesity experiment at thermoneutral temperature (33°C) and found that skin-specific Scd1 knockout (SKO) mice still remain resistant to obesity. To elucidate the metabolic changes in the skin that contribute to the obesity resistance and skin phenotype, we performed microarray analysis of skin gene expression in male SKO and control mice fed a standard rodent diet. We identified an extraordinary number of differentially expressed genes that support the previously documented histological observations of sebaceous gland hypoplasia, inflammation and epidermal hyperplasia in SKO mice. Additionally, transcript levels were reduced in skin of SKO mice for genes involved in fatty acid synthesis, elongation and desaturation, which may be attributed to decreased abundance of key transcription factors including SREBP1c, ChREBP and LXRα. Conversely, genes involved in cholesterol synthesis were increased, suggesting an imbalance between skin fatty acid and cholesterol synthesis. Unexpectedly, we observed a robust elevation in skin retinol, retinoic acid and retinoic acid-induced genes in SKO mice. Furthermore, SEB-1 sebocytes treated with retinol and SCD inhibitor also display an elevation in retinoic acid-induced genes. These results highlight the importance of monounsaturated fatty acid synthesis for maintaining retinol homeostasis and point to disturbed retinol metabolism as a novel contributor to the Scd1 deficiency-induced skin phenotype.

Background and Purpose-Adipose inflammation is crucial to the pathogenesis of metabolic disorders. This study aimed at identify the effects of stearoyl-CoA desaturase-1 (SCD1) on the inflammatory response of a paracrine network involving adipocytes, macrophages, and endothelial cells. Methods and Results-Loss of SCD1 in both genetic (Agouti) and diet-induced obesity (high-fat diet) mouse models prevented inflammation in white adipose tissue and improved its basal insulin signaling. In SCD1-deficient mice, white adipose tissue exhibited lower inflammation, with a reduced response to lipopolysaccharide in isolated adipocytes, but not in peritoneal macrophages. Mimicking the in vivo paracrine regulation of white adipose tissue inflammation, SCD1-deficient adipocyte-conditioned medium attenuated the induction of tumor necrosis factor (TNF) ␣/interleukin 1␤ gene expression in RAW264.7 macrophages and reduced the adhesion response in endothelial cells. We further demonstrated that the adipocyte-derived oleate (18:1n9), but not palmitoleate (16:

Repeated bouts of exercise condition muscle mitochondria to meet increased energy demand—an adaptive response associated with improved metabolic fitness. We found that the type 2 cytokine interleukin-13 (IL-13) is induced in exercising muscle, where it orchestrates metabolic reprogramming that preserves glycogen in favor of fatty acid oxidation and mitochondrial respiration. Exercise training–mediated mitochondrial biogenesis, running endurance, and beneficial glycemic effects were lost in Il13–/– mice. By contrast, enhanced muscle IL-13 signaling was sufficient to increase running distance, glucose tolerance, and mitochondrial activity similar to the effects of exercise training. In muscle, IL-13 acts through both its receptor IL-13Rα1 and the transcription factor Stat3. The genetic ablation of either of these downstream effectors reduced running capacity in mice. Thus, coordinated immunological and physiological responses mediate exercise-elicited metabolic adaptations that maximize muscle fuel economy.

Patients with advanced cancer and diabetes mellitus present a challenge to healthcare professionals. To establish how diabetes is currently being managed in these patients, we audited the care of patients who died in Cheltenham General Hospital over the previous 12 months with diagnoses of both diabetes mellitus and cancer. Management and monitoring of the diabetes was variable and there was little record of discussion between healthcare professionals and the patient or family regarding the diabetes. Thirty-two out of 42 patients continued to have blood sugar monitoring up to and including the day they died. We review the literature on this topic and suggest guidelines to help professionals to appropriately manage diabetes in the palliative setting at the end of life.

New Findings r What is the central question of this study?We wanted to determine the effect of three high-fat meals enriched with different fatty acids [monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs) or saturated fatty acids (SFAs)] on diet-induced thermogenesis and substrate oxidation in premenopausal women of normal weight. r What is the main finding and its importance?We found that a PUFA-rich high-fat meal led to a greater diet-induced thermogenesis in normal-weight premenopausal women compared with SFA-or MUFA-rich high-fat meals. The greater diet-induced thermogenesis for PUFA-rich meals could contribute to differences in long-term overall energy balance, and thus, weight maintenance. Substrate utilization was not different between treatments.The composition of fatty acids in a diet may differentially affect metabolism, thus playing a role in the development of obesity. Our aim was to study the effects of three high-fat (HF) meals with different degrees of saturation on diet-induced thermogenesis (DIT) and substrate oxidation in premenopausal women of normal weight. Fifteen healthy, normal-weight women, aged 18-35 years, participated in a randomized cross-over study, in which they consumed isocaloric HF meals (70% of energy from fat) rich in saturated fat (SFA; 40% of total energy), monounsaturated fat (MUFA; 42% of total energy) or polyunsaturated fat (PUFA; 42% of total energy). Indirect calorimetry was used to measure respiratory gases for a 5 h postprandial period. The data collected were used to determine respiratory exchange ratio for assessing substrate oxidation, as well as energy expenditure for the determination of DIT. The area under the curve for DIT following the PUFA-rich HF meal was greater than that of the SFA-or MUFA-rich HF meals [10.0 ± 0.7, 8.6 ± 0.8 and 8.9 ± 1.2 kcal (5 h) −1 (P = 0.02) for PUFA, MUFA and SFA, respectively]. No significant difference was found in respiratory exchange ratio (0.86 ± 0.01, 0.85 ± 0.01 and 0.85 ± 0.01 for PUFA-, MUFA-and SFA-rich HF meals, respectively) or substrate utilization following the three different HF meals (12.2 ± 1.0, 11.2 ± 0.5 and 11.6 ± 0.9 g for cumulative postprandial carbohydrate oxidation following the PUFA-, MUFA-and SFA-rich HF meals, respectively; and 3.8 ± 0.4, 4.1 ± 0.2 and 4.1 ± 0.3 g for cumulative fat oxidation of the PUFA-, MUFA-and SFA-rich HF meals, respectively). In conclusion, acute ingestion of a PUFA-rich HF meal induced a greater DIT in normal-weight women compared with SFA-or MUFA-rich HF meals. No significant differences were found for substrate utilization.