Recent studies have demonstrated that human stearoylCoA desaturase-1 (SCD1), a Δ9-desaturase that converts saturated fatty acids (SFA) into monounsaturated fatty acids, controls the rate of ...lipogenesis, cell proliferation and tumorigenic capacity in cancer cells. However, the biological function of stearoylCoA desaturase-5 (SCD5), a second isoform of human SCD that is highly expressed in brain, as well as its potential role in human disease, remains unknown. In this study we report that the constitutive overexpression of human SCD5 in mouse Neuro2a cells, a widely used cell model of neuronal growth and differentiation, displayed a greater n-7 MUFA-to-SFA ratio in cell lipids compared to empty-vector transfected cells (controls). De novo synthesis of phosphatidylcholine and cholesterolesters was increased whereas phosphatidylethanolamine and triacylglycerol formation was reduced in SCD5-expressing cells with respect to their controls, suggesting a differential use of SCD5 products for lipogenic reactions. We also observed that SCD5 expression markedly accelerated the rate of cell proliferation and suppressed the induction of neurite outgrowth, a typical marker of neuronal differentiation, by retinoic acid indicating that the desaturase plays a key role in the mechanisms of cell division and differentiation. Critical signal transduction pathways that are known to modulate these processes, such epidermal growth factor receptor (EGFR)Akt/ERK and Wnt, were affected by SCD5 expression. Epidermal growth factor-induced phosphorylation of EGFR, Akt and ERK was markedly blunted in SCD5-expressing cells. Furthermore, the activity of canonical Wnt was reduced whereas the non-canonical Wnt was increased by the presence of SCD5 activity. Finally, SCD5 expression increased the secretion of recombinant Wnt5a, a non-canonical Wnt, whereas it reduced the cellular and secreted levels of canonical Wnt7b. Our data suggest that, by a coordinated modulation of key lipogenic pathways and transduction signaling cascades, SCD5 participates in the regulation of neuronal cell growth and differentiation.
We sought to determine whether lipolysis, fatty acid (FA) mobilization, and plasma FA oxidation would remain elevated for
hours following isoenergetic exercise bouts of different intensities. Ten men ...and eight women received a primed-continuous
infusion of 1,1,2,3,3- 2 H 5 glycerol and continuous infusion of 1- 13 Cpalmitate to measure glycerol and plasma FA kinetics. On Day 1 (D1), participants were studied under one of three different
conditions, assigned in random order: (1) before, during and 3 h after 90 min of exercise at 45%
(E45), (2) before, during and 3 h after 60 min of exercise at 65%
(E65), and (3) in a time-matched sedentary control trial (C). For each condition, participants were studied by indirect calorimetry
the following morning as well (D2). Rate of appearance (Ra) of glycerol (Ra GL ) increased above C during exercise in men and women ( P < 0.05), was higher in E45 than E65 in men ( P < 0.05), and was not different between exercise intensities in women. During 3 h of postexercise recovery, Ra GL remained significantly elevated in men ( P < 0.05), but not women. FA Ra (Ra FA ) increased during exercise in men and women and was higher in E45 than E65 ( P < 0.05), and remained elevated during 3 h of postexercise recovery in both sexes ( P < 0.05), but with a greater relative increase in men than women ( P < 0.05). Plasma FA oxidation (Rox) increased during exercise with no difference between intensities, and it remained elevated
during 3 h of postexercise recovery in both sexes ( P < 0.05). Total lipid oxidation (Lox) was elevated in both sexes ( P < 0.05), but more in men during 3 h of postexercise recovery on D1 ( P < 0.05) and remained elevated on D2 in men ( P < 0.05), but not in women. There were no differences between E45 and E65 for postexercise energy substrate turnover or oxidation
in men and women as energy expenditure of exercise (EEE) was matched between bouts. We conclude that the impact of exercise
upon lipid metabolism persists into recovery, but that women depend more on lipid during exercise whereas, during recovery,
lipid metabolism is accentuated to a greater extent in men.
Abstract The mdx mouse is a model for Duchenne muscular dystrophy. The fatty acid (FA) composition in dystrophic muscle could potentially impact the disease severity. We tested FA profiles in ...skeletal muscle phospholipid (PL) and triglyceride in mdx and control (con) mice to assess associations with disease state as well as correlations with grip strength (which is lower in mdx) and serum creatine kinase (CK, which is elevated in mdx). Compared with con, mdx PL contained less docosahexaenoic acid ( P < .001) and more linoleic acid ( P = .001). Docosahexaenoic acid contents did not correlate with strength or serum CK. Linoleic acid content in PL was positively correlated with CK in mdx ( P < .05) but not con. α -Linolenic acid content in PL was positively correlated with strength in mdx ( P < .05) but not con. The FA profile in triglyceride showed less difference between groups and far less predictive ability for disease markers. We conclude that profiling the FA composition of tissue lipids (particularly PL) can be a useful strategy for generating novel biomarkers and potential therapeutic targets in muscle diseases and likely other pathological conditions as well. Specifically, the present results have indicated potential benefits of raising content of particular n-3 FAs (especially α -linolenic acid) and reducing content of particular n-6 FAs (linoleic acid) in PL of dystrophic muscle.
Aging is characterized by increases in inflammation and oxidative stress, conditions that are exacerbated by environmental factors such as diet. In this study, we investigated the effects of a ...trans-fatty acid (TFA) diet on the liver in adult (25 wk) and old (60 wk) senescence-accelerated mice (SAMP8 strain) of both sexes. Our goal was to assess the effects of the diet on protein markers of inflammation and oxidative stress in the liver.
Male and female mice were placed on life-long diets containing similar amounts of total fat (17%), with differing amounts of TFA: 2% (moderate TFA group) or 0.2% of total energy from TFA (control diet group). At the indicated ages, livers were harvested and evaluated for markers of inflammation and oxidative stress, as well as for enzymes of fat metabolism via immunoblotting. Relative densities of protein bands were determined and compared via a three-factor ANOVA.
Compared to males, females demonstrated significantly lower inflammatory protein expression (ICAM-1, MCP-1, COX-2), along with lower expression of the DNA damage marker, Gadd153, and the oxidative stress marker, HO-1. Female mice demonstrated higher expression of antioxidant enzymes (SOD-1, SOD-2, and Ref-1) and lipogenic enzymes (FASN, ACLY) compared to male mice. While HO-1 was elevated in the female mice fed the TFA diet compared to controls, the diet did not affect other markers of oxidative stress or inflammation. However, the diet was associated with significant increases in FASN and ACLY in adult (25 wk) male mice.
Our results suggest sexually dimorphic protein expression in the liver, with female mice demonstrating lower inflammation and increased oxidative stress defenses. Additionally, considering that FASN and ACLY contribute to hepatic lipogenesis, our results suggest a potential mechanism for the dyslipidemia in adult male mice that is associated with TFA diets.
When consumed separately, whey protein (WP) is more rapidly absorbed into circulation than casein (Cas), which prompted the concept of rapid and slow dietary protein. It is unclear whether these ...proteins have similar metabolic fates when coingested as in milk. We determined the rate of appearance across the splanchnic bed and the rate of disappearance across the leg of phenylalanine (Phe) from coingested, intrinsically labeled WP and Cas. Either ¹⁵NPhe or ¹³C-ring C₆Phe was infused in lactating cows, and the labeled WP and Cas from their milk were collected. To determine the fate of Phe derived from different protein sources, 18 healthy participants were studied after ingestion of one of the following: 1) ¹⁵NWP, ¹³CCas, and lactose; 2) ¹³CWP, ¹⁵NCas, and lactose; 3) lactose alone. At 80-120 min, the rates of appearance (R(a)) across the splanchnic bed of Phe from WP and Cas were similar 0.068 ± 0.010 vs. 0.070 ± 0.009%/min; not significant (ns). At time 220-260 min, Phe appearance from WP had slowed (0.039 ± 0.008%/min, P < 0.05) whereas Phe appearance from Cas was sustained (0.068 ± 0.013%/min). Similarly, accretion rates across the leg of Phe absorbed from WP and Cas were not different at 80-120 min (0.011 ± 0.002 vs. 0.012 ± 0.003%/min; ns), but they were significantly lower for WP (0.007 ± 0.002%/min) at 220-260 min than for Cas (0.013 ± 0.002%/min) at 220-260 min. Early after meal ingestion, amino acid absorption and retention across the leg were similar for WP and Cas, but as rates for WP waned, absorption and assimilation into skeletal muscle were better retained for Cas.
We investigated the effects of two exercise modalities on postprandial triglyceride (TG) and free fatty acid (FFA) metabolism. Sedentary, obese women were studied on three occasions in randomized ...order: endurance exercise for 60 min at 60-65% aerobic capacity (E), ~60 min high-intensity resistance exercise (R), and a sedentary control trial (C). After exercise, a liquid-mixed meal containing U-(13)Cpalmitate was consumed, and subjects were studied over 7 h. Isotopic enrichment (IE) of plasma TG, plasma FFA, and breath carbon dioxide compared with meal IE indicated the contribution of dietary fat to each pool. Total and endogenously derived plasma TG content was reduced significantly in both E and R compared with C (P < 0.05), with no effect of exercise on circulating exogenous (meal-derived) TG content. Exogenous plasma FFA content was increased significantly following both E and R compared with C (P < 0.05), whereas total and endogenous FFA concentrations were elevated only in E (P < 0.05) compared with C. Fatty acid (FA) oxidation rates were increased significantly after E and R compared with C (P < 0.05), with no difference between exercise modalities. The present results indicate that E and R may be equally effective in reducing postprandial plasma TG concentration and enhancing lipid oxidation when the exercise sessions are matched for duration rather than for energy expenditure. Importantly, tracer results indicated that the reduction in postprandial lipemia after E and R exercise bouts is not achieved by enhanced clearance of dietary fat but rather, is achieved by reduced abundance of endogenous FA in plasma TG.
We investigated age and sex effects and determined whether androgen replacement in elderly individuals (greater-than-or-equal60 yr) could augment protein synthesis. Thirty young men and 32 young ...women (18-31 yr) were studied once, whereas 87 elderly men were studied before and after 1 yr of treatment with 5 mg/day testosterone (T), 75 mg/day dehydroepiandrosterone (DHEA), or placebo (P); and 57 elderly women were studied before and after 1 yr of treatment with 50 mg/day DHEA or P. ¹⁵NPhenylalanine and ²H₄tyrosine tracers were infused, with measurements in plasma and vastus lateralis muscle. Whole-body protein synthesis per fat-free mass and muscle protein fractional synthesis rate (FSR) were lower in elderly than in young individuals (P<0.001), not significantly affected by hormone treatments, and higher in women than in men (P<0.0001), with no sex x age interaction. In regression analyses, peak O₂ consumption (VO₂peak), resting energy expenditure (REE), and sex were independently associated with muscle FSR, as were VO₂peak, REE, and interactions of sex with insulin-like growth factor-II and insulin for whole-body protein synthesis. Women maintain higher protein synthesis than men across the lifespan as rates decline in both sexes, and neither full replacement of DHEA (in elderly men and women) nor partial replacement of bioavailable T (in elderly men) is able to amend the age-related declines.--Henderson, G. C., Dhatariya, K., Ford, G. C., Klaus, K. A., Basu, R., Rizza, R. A., Jensen, M. D., Khosla, S., O'Brien, P., Nair, K. S. Higher muscle protein synthesis in women than men across the lifespan, and failure of androgen administration to amend age-related decrements.
Lipid metabolism plays a critical role in health, and there are a variety of methodologies available to investigators to determine how rates of metabolic processes respond to drugs and other ...interventions aimed at altering lipid metabolism. Commonly the abundance of lipids in the body is measured (e.g., plasma lipoprotein concentrations), but this static measure offers only a limited view on the dynamics and complexity of lipid metabolism as it pertains to health and disease. The synthesis and clearance rates of lipoproteins provide critical information pertaining to cardiovascular disease, and the mobilization of triglyceride and fatty acids and partitioning between metabolic fates affects the body composition and other aspects of health. Various techniques are available to measure the kinetics of lipid metabolism including stable isotope approaches, radio-isotope approaches, and non-isotopic approaches. The focus of this review is to describe various techniques for evaluating lipid kinetics in animal models and humans using isotopes as well as other techniques, and recent advances are highlighted.
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