Improving glycogenesis in Streptozocin (STZ) diabetic mice after administration of green algae Chlorella

Chlorella, a type of unicellular fresh water algae, has been a popular foodstuff in Japan and Taiwan. Studies have shown the hypoglycemic effects of Chlorella in alloxan-induced and Streptozocin (STZ)-induced diabetic animals. However, the mechanisms by which Chlorella treatment affects blood glucose homeostasis have not been studied. Diabetes in ICR mice was induced by injection of STZ. Lipogenesis in vivo was measured by incorporating 3H-H2O into lipids in brown and white adipose tissues. Glucose uptake in the liver and soleus muscles was measured by assaying 2-deoxy-D-[1,2-3H] glucose levels. The effects of Chlorella on serum non-esterified fatty acids (NEFA) were measured with commercial assay kits. Insulin-stimulated lipogenic rates in brown and white adipose tissues were unaffected by Chlorella. However, Chlorella increased 2-deoxyglucose uptake in the livers and soleus muscles in normal and STZ mice compared to that in their respective controls (p < 0.01). In addition, fasting NEFA levels were lower in Chlorella-treated STZ mice compared to H2O-treated STZ mice (p < 0.005). The current results suggest that the hypoglycemic effects of Chlorella are due to an enhancement of glucose uptake in the liver and in soleus muscles. The improved insulin sensitivity after Chlorella treatment could be also due to lower NEFA levels, since insulin sensitivity is usually blunted by elevated NEFA in diabetes.     

Co-ordination of hepatic and adipose tissue lipid metabolism after oral glucose.

The integration of lipid metabolism in the splanchnic bed and in subcutaneous adipose tissue before and after ingestion of a 75 g glucose load was studied by Fick's principle in seven healthy subjects. Six additional subjects were studied during a hyperinsulinemic euglycemic clamp. Release of non-esterified fatty acids (NEFA) from adipose tissue and splanchnic NEFA extraction followed a similar time-course after oral glucose, and there was a highly significant relationship between adipose tissue NEFA release and splanchnic NEFA uptake. There was no immediate inhibition of splanchnic very low density lipoprotein (VLDL)-triacylglycerol (TAG) output when plasma insulin levels increased after glucose. Adipose tissue extraction of VLDL-TAG tended to vary in time in a manner similar to splanchnic VLDL-TAG output and the two were significantly related. The area-under-curves (AUC) for splanchnic extraction of NEFA was significantly lower than that for output of VLDL, implying depletion of hepatic TAG stores during the experiment. In the hyperinsulinemic clamp experiments, there was on average suppression of splanchnic VLDL-TAG output although between-person variability was marked. This suppression could be explained by a very low supply of NEFA during the clamp.We conclude that there is an integrated pattern of metabolism in splanchnic and adipose tissues in the postabsorptive and post-glucose states. Flux of NEFA from adipose tissue drives splanchnic NEFA uptake. Splanchnic VLDL-TAG secretion appears to be regulated by a number of factors and in turn controls TAG extraction in adipose tissue. Insulin does not seem to play a key role in the acute regulation of hepatic VLDL metabolism under these particular conditions in vivo.     

Metabolic characteristics of human subcutaneous abdominal adipose tissue after overnight fast

Subcutaneous abdominal adipose tissue is one of the largest fat depots and contributes the major proportion of circulating nonesterified fatty acids (NEFA). Little is known about aspects of human adipose tissue metabolism in vivo other than lipolysis. Here we collated data from 331 experiments in 255 healthy volunteers over a 23-year period, in which subcutaneous abdominal adipose tissue metabolism was studied by measurements of arterio-venous differences after an overnight fast. NEFA and glycerol were released in a ratio of 2.7:1, different (P < 0.001) from the value of 3.0 that would indicate no fatty acid re-esterification. Fatty acid re-esterification was 10.2 ± 1.4%. Extraction of triacylglycerol (TG) (fractional extraction 5.7 ± 0.4%) indicated intravascular lipolysis by lipoprotein lipase, and this contributed 21 ± 3% of the glycerol released. Glucose uptake (fractional extraction 2.6 ± 0.3%) was partitioned around 20-25% for provision of glycerol 3-phosphate and 30% into lactate production. There was release of lactate and pyruvate, with extraction of the ketone bodies 3-hydroxybutyrate and acetoacetate, although these were small numerically compared with TG and glucose uptake. NEFA release (expressed per 100 g tissue) correlated inversely with measures of fat mass (e.g., with BMI, r(s) = -0.24, P < 0.001). We examined within-person variability. Systemic NEFA concentrations, NEFA release, fatty acid re-esterification, and adipose tissue blood flow were all more consistent within than between individuals. This picture of human adipose tissue metabolism in the fasted state should contribute to a greater understanding of adipose tissue physiology and pathophysiology.     

Lipid-heparin infusion suppresses the IL-10 response to trauma in subcutaneous adipose tissue in humans

An imbalance between pro‐ and anti‐inflammatory cytokine productions in adipose tissue is thought to contribute to chronic, systemic, low‐grade inflammation and consequently to an increased risk of cardiovascular complications in obese and type 2 diabetic patients. Nonesterified fatty acids (NEFA), whose serum levels are elevated in such patients, have been shown to interfere with cytokine production in vitro. In order to evaluate the effects of elevated NEFA levels on cytokine production in adipose tissue in vivo we used an 18‐gauge open‐flow microperfusion (OFM) catheter to induce local inflammation in the subcutaneous adipose tissue (SAT) of healthy volunteers and to sample interstitial fluid (IF) specifically from the inflamed tissue. In two crossover studies, nine subjects received either an intravenous lipid‐heparin infusion to elevate circulating NEFA levels or saline over a period of 28 h. The former increased the circulating levels of triglycerides (TGs), NEFA, glucose, and insulin over the study period. NEFA effects on locally induced inflammation were estimated by measuring the levels of a panel adipokines in the OFM probe effluent. Interleukin‐6 (IL‐6), IL‐8, tumor necrosis factor‐α (TNF‐α) and monocyte chemoattractant protein‐1 (MCP‐1) levels increased during the study period but were not affected by lipid‐heparin infusion. In contrast, the level of IL‐10, an anti‐inflammatory cytokine, was significantly reduced during the final hour of lipid‐heparin infusion (saline: 449.2 ± 105.9 vs. lipid‐heparin: 65.4 ± 15.4 pg/ml; P = 0.02). These data provide the first in vivo evidence that elevated NEFA can modulate cytokine production by adipose tissue.     

Beneficial Effects of Calcitriol on Hypertension,Glucose Intolerance,Impairment of Endothelium-Dependent Vascular Relaxation,and Visceral Adiposity in Fructose-Fed Hypertensive Rats

Besides regulating calcium homeostasis, the effects of vitamin D on vascular tone and metabolic disturbances remain scarce in the literature despite an increase intake with high-fructose corn syrup worldwide. We investigated the effects of calcitriol, an active form of vitamin D, on vascular relaxation, glucose tolerance, and visceral fat pads in fructose-fed rats. Male Wistar-Kyoto rats were divided into 4 groups (n = 6 per group). Group Con: standard chow diet for 8 weeks; Group Fru: high-fructose diet (60% fructose) for 8 weeks; Group Fru-HVD: high-fructose diet as Group Fru, high-dose calcitriol treatment (20 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding; and Group Fru-LVD: high-fructose diet as Group Fru, low-dose calcitriol treatment (10 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding. Systolic blood pressure was measured twice a week by the tail-cuff method. Blood was examined for serum ionized calcium, phosphate, creatinine, glucose, triglycerides, and total cholesterol. Intra-peritoneal glucose intolerance test, aortic vascular reactivity, the weight of visceral fat pads, adipose size, and adipose angiotensin II levels were analyzed at the end of the study. The results showed that the fructose-fed rats significantly developed hypertension, impaired glucose tolerance, heavier weight and larger adipose size of visceral fat pads, and raised adipose angiotensin II expressions compared with the control rats. High- and low-dose calcitriol reduced modestly systolic blood pressure, increased endothelium-dependent aortic relaxation, ameliorated glucose intolerance, reduced the weight and adipose size of visceral fat pads, and lowered adipose angiotensin II expressions in the fructose-fed rats. However, high-dose calcitriol treatment mildly increased serum ionized calcium levels (1.44 ± 0.05 mmol/L). These results suggest a protective role of calcitriol treatment on endothelial function, glucose tolerance, and visceral adiposity in fructose-fed rats.     

No Evidence for a Role of Adipose Tissue-Derived Serum Amyloid A in the Development of Insulin Resistance or Obesity-Related Inflammation in hSAA1+/? Transgenic Mice

Obesity is associated with a low-grade inflammation including moderately increased serum levels of the acute phase protein serum amyloid A (SAA). In obesity, SAA is mainly produced from adipose tissue and serum levels of SAA are associated with insulin resistance. SAA has been described as a chemoattractant for inflammatory cells and adipose tissue from obese individuals contains increased numbers of macrophages. However, whether adipose tissue-derived SAA can have a direct impact on macrophage infiltration in adipose tissue or the development of insulin resistance is unknown. The aim of this study was to investigate the effects of adipose tissue-derived SAA1 on the development of insulin resistance and obesity-related inflammation. We have previously established a transgenic mouse model expressing human SAA1 in the adipose tissue. For this report, hSAA1^+/− transgenic mice and wild type mice were fed with a high fat diet or normal chow. Effects of hSAA1 on glucose metabolism were assessed using an oral glucose tolerance test. Real-time PCR was used to measure the mRNA levels of macrophage markers and genes related to insulin sensitivity in adipose tissue. Cytokines during inflammation were analyzed using a Proinflammatory 7-plex Assay. We found similar insulin and glucose levels in hSAA1 mice and wt controls during an oral glucose tolerance test and no decrease in mRNA levels of genes related to insulin sensitivity in adipose tissue in neither male nor female hSAA1 animals. Furthermore, serum levels of proinflammatory cytokines and mRNA levels of macrophage markers in adipose tissue were not increased in hSAA1 mice. Hence, in this model we find no evidence that adipose tissue-derived hSAA1 influences the development of insulin resistance or obesity-related inflammation.     

Progeny of high muscling sires have reduced muscle response to adrenaline in sheep

This study investigated the impact of variation in Australian sheep breeding values (ASBVs) for yearling eye muscle depth (YEMD) within Merino and Poll Dorset sires on intermediary metabolism of progeny. Specifically, the change in the blood concentrations of lactate, non-esterified fatty acids (NEFA) and glucose in response to administration of an exogenous dose of adrenaline was studied. The experiment used 20 Merino and Merino cross Poll Dorset mixed sex sheep. The sires were selected across a range of YEMD ASBVs. The sheep were fitted with indwelling jugular catheters and administered seven levels of adrenaline over a period of 4 days at 4 months of age (0.1, 0.2, 0.4, 0.6, 0.9, 1.2 and 1.6 μg/kg liveweight (LW)) and 16 months of age (0.1, 0.2, 0.6, 1.2, 1.8, 2.4 and 3.0 μg/kg LW). A total of 16 blood samples were collected between -30 min and 130 min relative to administration of the adrenaline challenge and were later measured for the plasma concentrations of lactate, NEFA and glucose. These data were then used to calculate the time to maximum substrate concentration, the maximum concentration and the area under curve (AUC) between 0 and 10 min, thus reflecting the substrate's response to exogenous adrenaline. Selection for muscling led to decreased muscle response due to adrenaline, as indicated by lower maximum concentrations and AUC for lactate. The muscles' response to adrenaline was more prominent at 16 months of age than at 4 months of age. Thus, animals selected for increased muscling have lower levels of glycogenolysis in situations where endogenous adrenaline levels are increased like pre-slaughter. This may minimise the risk of poor meat quality in these animals, as they will express higher muscle concentrations of glycogen at slaughter. Adipose tissue was more sensitive to adrenaline in young lambs from high YEMD sires. This shows that high muscled growing lambs utilise their adipose tissue deposits in times of stress to produce energy. This may explain the phenotypic leanness of these animals. Blood glucose levels that are indicative of liver response to adrenaline decreased with selection for muscling. This response may indicate a potential limiting of glucose that is available within animals selected for muscling, leanness and growth for brain function.     

Differential modulation of white adipose tissue endocannabinoid levels by n-3 fatty acids in obese mice and type 2 diabetic patients

n-3 polyunsaturated fatty acids (n-3 PUFA) might regulate metabolism by lowering endocannabinoid levels. We examined time-dependent changes in adipose tissue levels of endocannabinoids as well as in parameters of glucose homeostasis induced by n-3 PUFA in dietary-obese mice, and compared these results with the effect of n-3 PUFA intervention in type 2 diabetic (T2DM) subjects. Male C57BL/6J mice were fed for 8, 16 or 24?weeks a high-fat diet alone (cHF) or supplemented with n-3 PUFA (cHF?+?F). Overweight/obese, T2DM patients on metformin therapy were given for 24?weeks corn oil (Placebo; 5?g/day) or n-3 PUFA concentrate as above (Omega-3; 5?g/day). Endocannabinoids were measured by liquid chromatography-tandem mass-spectrometry. Compared to cHF-fed controls, the cHF?+?F mice consistently reduced 2-arachidonoylglycerol (up to ~2-fold at week 24) and anandamide (~2-fold) in adipose tissue, while the levels of endocannabinoid-related anti-inflammatory molecules N-eicosapentaenoyl ethanolamine (EPEA) and N-docosahexaenoyl ethanolamine (DHEA) increased more than ~10-fold and ~8-fold, respectively. At week 24, the cHF?+?F mice improved glucose tolerance and fasting blood glucose, the latter being positively correlated with adipose 2-arachidonoylglycerol levels only in obese cHF-fed controls, like fasting insulin and HOMA-IR. In the patients, n-3 PUFA failed to reduce 2-arachidonoylglycerol and anandamide levels in adipose tissue and serum, but they increased both adipose tissue and serum levels of EPEA and DHEA. In conclusion, the inability of n-3 PUFA to reduce adipose tissue and serum levels of classical endocannabinoids might contribute to a lack of beneficial effects of these lipids on glucose homeostasis in T2DM patients.     

Anti-obesity and anti-diabetic actions of a beta 3-adrenoceptor agonist, BRL 26830A, in yellow KK mice.

The anti-obesity and anti-diabetic actions of BRL 26830A, beta 3-adrenoceptor agonist, (2 mg/kg administered intramuscularly daily for 2 weeks) were evaluated in obese diabetic Yellow KK mice and C57B1 control mice. The following parameters were compared in the treated vs. control animals: brown adipose tissue (BAT) thermogenesis, resting metabolic rate (RMR), insulin receptors in adipocytes, and blood glucose and serum insulin levels during a glucose overloading test. BRL 26830A significantly increased BAT thermogenesis and RMR but it decreased the amount of white adipose tissue without affecting food intake. Those actions contributed to the mitigation of obesity in Yellow KK mice. BRL 26830A also increased the concentration of insulin receptors and decreased the levels of serum insulin and blood glucose during the glucose overloading test in Yellow KK mice. In the glucose overloading test performed one hour after BRL 26830A injection, insulin secretion was significantly increased and the blood glucose level was markedly decreased in both groups. These observations suggest that BRL 26830A possesses anti-obesity and anti-diabetic actions and consequently may be useful for treating obesity as well as non-insulin-dependent diabetes mellitus with obesity.     

Role of adipose tissue in methionine–choline-deficient model of non-alcoholic steatohepatitis (NASH)

Methionine–choline-deficient (MCD) diet is a widely used dietary model of non-alcoholic steatohepatitis (NASH) in rodents. However, the contribution of adipose tissue to MCD-induced steatosis, and inflammation as features of NASH are not fully understood. The goal of this study was to elucidate the role of adipose tissue fatty acid (FA) metabolism, adipogenesis, lipolysis, inflammation and subsequent changes in FA profiles in serum and liver in the pathogenesis of steatohepatitis. We therefore fed ob/ob mice with control or MCD diet for 5 weeks. MCD-feeding increased adipose triglyceride lipase and hormone sensitive lipase activities in all adipose depots which may be attributed to increased systemic FGF21 levels. The highest lipase enzyme activity was exhibited by visceral WAT. Non-esterified fatty acid (NEFA)-18:2n6 was the predominantly elevated FA species in serum and liver of MCD-fed ob/ob mice, while overall serum total fatty acid (TFA) composition was reduced. In contrast, an overall increase of all FA species from TFA pool was found in liver, reflecting the combined effects of increased FA flux to liver, decreased FA oxidation and decrease in lipase activity in liver. NAFLD activity score was increased in liver, while WAT showed no changes and BAT showed even reduced inflammation. Conclusion: This study demonstrates a key role for adipose tissue lipases in the pathogenesis of NASH and provides a comprehensive lipidomic profiling of NEFA and TFA homeostasis in serum and liver. Our findings provide novel mechanistic insights for the role of WAT in progression of MCD-induced liver injury.     

Deletion of Hypoxia-Inducible Factor-1α in Adipocytes Enhances Glucagon-Like Peptide-1 Secretion and Reduces Adipose Tissue Inflammation

It is known that obese adipose tissues are hypoxic and express hypoxia-inducible factor (HIF)-1α. Although some studies have shown that the expression of HIF-1α in adipocytes induces glucose intolerance, the mechanisms are still not clear. In this study, we examined its effects on the development of type 2 diabetes by using adipocyte-specific HIF-1α knockout (ahKO) mice. ahKO mice showed improved glucose tolerance compared with wild type (WT) mice. Macrophage infiltration and mRNA levels of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor α (TNFα) were decreased in the epididymal adipose tissues of high fat diet induced obese ahKO mice. The results indicated that the obesity-induced adipose tissue inflammation was suppressed in ahKO mice. In addition, in the ahKO mice, serum insulin levels were increased under the free-feeding but not the fasting condition, indicating that postprandial insulin secretion was enhanced. Serum glucagon-like peptide-1 (GLP-1) levels were also increased in the ahKO mice. Interestingly, adiponectin, whose serum levels were increased in the obese ahKO mice compared with the obese WT mice, stimulated GLP-1 secretion from cultured intestinal L cells. Therefore, insulin secretion may have been enhanced through the adiponectin-GLP-1 pathway in the ahKO mice. Our results suggest that the deletion of HIF-1α in adipocytes improves glucose tolerance by enhancing insulin secretion through the GLP-1 pathway and by reducing macrophage infiltration and inflammation in adipose tissue.     

Chronic leptin administration increases serum NEFA in the pig and differentially regulates PPAR expression in adipose tissue

Two in vivo studies were conducted with pigs to determine the effects of exogenous leptin on the expression of peroxisome proliferator activated receptors (PPAR), and on serum concentrations of selected metabolites and hormones. Initially, leptin was administered i.m. to young pigs for 15 days at 0 (control), 0.003 (low), 0.01 (medium) and 0.03 (high) mg. kg(-1). day(-1). There was no leptin effect on serum glucose (P > 0.84), triglycerides (P > 0.69), non-esterified fatty acids (NEFA, P > 0.53), or glycerol (P > 0.33). Leptin at the intermediate and high doses depressed adipose expression of both PPARgamma1 (P < 0.06) and PPARgamma2 (P < 0.01). In a second study, we used a paired-feeding experimental design to determine the effects of a higher dose of leptin (0.05 mg. kg(-1). day(-1)) on serum metabolites and PPAR expression in selected tissues. At this dose, leptin increased (P < 0.0001) serum NEFA concentrations relative to both the ad libitum and pair-fed control groups. However, in this study, there was no difference in the expression of PPARgamma1 in adipose tissue, but PPARgamma2 mRNA was upregulated by leptin (P < 0.08). In contrast, leptin had no impact on the expression of PPARalpha in liver, skeletal muscle or adipose tissue. Adipose tissue explants were also incubated with leptin to assess the effect on PPARgamma expression, in vitro. The abundance of PPARgamma1 mRNA (P < 0.05) was increased after 24 hr of exposure, but the effect of leptin on gamma2 was not significant (P > 0.24). The lipolytic effect of leptin was also evaluated in vitro using isolated adipocytes. In keeping with the increase in serum NEFA concentrations in vivo, leptin stimulated lipolysis in vitro, increasing glycerol concentrations in the medium to about 219% of that in basal (non-treated) culture medium after 8 hr of incubation. Collectively, the data presented herein indicate that leptin modulates lipid metabolism in the pig, but that PPARalpha expression is not a parallel target of leptin as it is in rodent models. The regulation of PPARgamma by leptin seems complex in that it varied in relation to dose in vivo, and may be impacted by in vitro vs. in vivo circumstances.     

Fluctuations in energy-related metabolites during the peri-parturition period in Lori-Bakhtiari ewes

This study describes the fluctuations in serum energy-related metabolites during a period of 2 weeks before, to 2 weeks after parturition in Lori-Bakhtiari ewes. The effect of parity was also studied. Blood profiles were determined in 60 healthy pregnant ewes with single (n = 30) and twin (n = 30) lambings. Blood was collected from each ewe on days 14 and 7 prepartum, and days 7 and 14 postpartum to determine the serum non-esterified fatty acid (NEFA), β-hydroxybutyrate (BHBA), glucose, cholesterol, blood urea nitrogen (BUN) and calcium (Ca) levels. The age of the ewes had no significant effect on the energy metabolism indicators. Serum NEFA, BHBA, glucose, BUN and calcium concentrations recorded peak levels 7 days before parturition. However, NEFA and BHBA recorded significant changes (P < 0.05) during the peri-parturition period. All metabolites changed significantly in ewes carrying twin-bearing ewes, compared to single-bearing ewes. Serum BHBA concentrations recorded positive correlations with the serum NEFA (P < 0.01) and cholesterol (P < 0.05), while blood glucose had negative correlations (P < 0.01) with NEFA, BHBA and Ca. Blood NEFA and BHBA recorded positive correlations (P < 0.05) with the BUN levels and negative correlations (P < 0.05) with Ca. The results showed that blood NEFA and BHBA levels are sensitive indicators of the energy balance during the peri-parturition period in ewes.     

Adipose triglyceride lipase expression and fasting regulation are differently affected by cold exposure in adipose tissues of lean and obese Zucker rats

Adipose triglyceride lipase (ATGL) hydrolyzes triacylglycerols to diacylglycerols in the first step of lipolysis, providing substrates for hormone-sensitive lipase (HSL). Here we studied whether ATGL messenger RNA (mRNA) and protein levels were affected by 24-h cold exposure in different white adipose tissue depots and in interscapular brown adipose tissue of lean and obese Zucker rats submitted to feeding and 14-h fasting conditions. HSL mRNA expression was also studied in selected depots. In both lean and obese rats, as a general trend, cold exposure increased ATGL mRNA and protein levels in the different adipose depots, except in the brown adipose tissue of lean animals, where a decrease was observed. In lean rats, cold exposure strongly improved fasting up-regulation of ATGL expression in all the adipose depots. Moreover, in response to fasting, in cold-exposed lean rats, there was a stronger positive correlation between circulating nonesterified fatty acids (NEFA) and ATGL mRNA levels in the adipose depots and a higher percentage increase of circulating NEFA in comparison with control animals not exposed to cold. In obese rats, fasting-induced up-regulation of ATGL was impaired and was not improved by cold. The effects of obesity and cold exposure on HSL mRNA expression were similar to those observed for ATGL, suggesting common regulatory mechanisms for both proteins. Thus, cold exposure increases ATGL expression and improves its fasting-up-regulation in adipose tissue of lean rats. In obese rats, cold exposure also increases ATGL expression but fails to improve its regulation by fasting, which could contribute to the increased difficulty for mobilizing lipids in these animals.     

Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle.

Hormone-sensitive lipase (HSL) is believed to play an important role in the mobilization of fatty acids from triglycerides (TG), diglycerides, and cholesteryl esters in various tissues. Because HSL-mediated lipolysis of TG in adipose tissue (AT) directly feeds non-esterified fatty acids (NEFA) into the vascular system, the enzyme is expected to affect many metabolic processes including the metabolism of plasma lipids and lipoproteins. In the present study we examined these metabolic changes in induced mutant mouse lines that lack HSL expression (HSL-ko mice). During fasting, when HSL is normally strongly induced in AT, HSL-ko animals exhibited markedly decreased plasma concentrations of NEFA (-40%) and TG (-63%), whereas total cholesterol and HDL cholesterol levels were increased (+34%). Except for the increased HDL cholesterol concentrations, these differences were not observed in fed animals, in which HSL activity is generally low. Decreased plasma TG levels in fasted HSL-ko mice were mainly caused by decreased hepatic very low density lipid lipoprotein (VLDL) synthesis as a result of decreased NEFA transport from the periphery to the liver. Reduced NEFA transport was also indicated by a depletion of hepatic TG stores (-90%) and strongly decreased ketone body concentrations in plasma (-80%). Decreased plasma NEFA and TG levels in fasted HSL-ko mice were associated with increased fractional catabolic rates of VLDL-TG and an induction of the tissue-specific lipoprotein lipase (LPL) activity in cardiac muscle, skeletal muscle, and white AT. In brown AT, LPL activity was decreased. Both increased VLDL fractional catabolic rates and increased LPL activity in muscle were unable to provide the heart with sufficient NEFA, which led to decreased tissue TG levels in cardiac muscle. Our results demonstrate that HSL deficiency markedly affects the metabolism of TG-rich lipoproteins by the coordinate down-regulation of VLDL synthesis and up-regulation of LPL in muscle and white adipose tissue. These changes result in an "anti-atherogenic" lipoprotein profile.     

Lipolytic signaling in response to acute exercise is altered in female mice following ovariectomy

Impaired ovarian function alters lipid metabolism, ultimately resulting in increased visceral fat mass. Currently, we have a poor understanding of alterations in signaling events regulating lipolysis after ovarian function declines. The purpose of this study was to determine if cellular mechanisms regulating lipolysis are altered in mice after ovariectomy (OVX) and if OVX mice exhibit impaired lipolytic signaling when stimulated by acute exercise. SHAM and OVX mice were divided into two groups: control (SHAM cont; OVX cont) or acute treadmill exercise (SHAM ex; OVX ex). The omental/mesenteric (O/M) fat mass of all OVX mice was significantly greater than the SHAM mice. Serum glycerol and blood glucose levels were significantly elevated in OVX cont compared to SHAM cont. Treadmill exercise increased serum glycerol levels only in SHAM mice, with no exercise-induced change detected in OVX mice. NEFA levels were significantly elevated by acute exercise in the SHAM and OVX groups. In O/M fat from both OVX groups there were significant increases in cytosolic ATGL and PLIN2 in the fat cake fraction with concurrent reductions in PLIN1 in the fat cake compared to SHAM. Further, exercise induced significant increases in HSL Ser660 phosphorylation in SHAM mice, but not OVX mice. This suggests that reduced ovarian function has significant effects on critical lipolytic cell signaling mechanisms in O/M adipose tissue.     

Increase in epinephrine-induced responsiveness during microgravity simulated by head-down bed rest in humans.

The epinephrine (Epi)-induced effects on the sympathetic nervous system (SNS) and metabolic functions were studied in men before and during a decrease in SNS activity achieved through simulated microgravity. Epi was infused at 3 graded rates (0.01, 0.02, and 0. 03 microg. kg(-1). min(-1) for 40 min each) before and on the fifth day of head-down bed rest (HDBR). The effects of Epi on the SNS (assessed by plasma norepinephrine levels and spectral analysis of systolic blood pressure and heart rate variability), on plasma levels of glycerol, nonesterified fatty acids (NEFA), glucose and insulin, and on energy expenditure were evaluated. HDBR decreased urinary norepinephrine excretion (28.1 +/- 4.2 vs. 51.5 +/- 9.1 microg/24 h) and spectral variability of systolic blood pressure in the midfrequency range (16.3 +/- 1.9 vs. 24.5 +/- 0.9 normalized units). Epi increased norepinephrine plasma levels (P < 0.01) and spectral variability of systolic blood pressure (P < 0.009) during, but not before, HDBR. No modification of Epi-induced changes in heart rate and systolic and diastolic blood pressures were observed during HDBR. Epi increased plasma glucose, insulin, and NEFA levels before and during HDBR. During HDBR, the Epi-induced increase in plasma glycerol and lactate levels was more pronounced than before HDBR (P < 0.005 and P < 0.001, respectively). Epi-induced energy expenditure was higher during HDBR (P < 0.02). Our data suggest that the increased effects of Epi during simulated microgravity could be related to both the increased SNS response to Epi infusion and/or to the beta-adrenergic receptor sensitization of end organs, particularly in adipose tissue and skeletal muscle.     

Effect of 5-Campestenone (24-methylcholest-5-en-3-one) on Zucker diabetic fatty rats as a type 2 diabetes mellitus model.

We examined the therapeutic effects of dietary exposure to 5-campestenone (24-methylcholest-5-en-3-one), an enone derivative of campesterol, in Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes mellitus. Dietary 0.6 % exposure to 5-campestenone caused marked reduction in hemoglobin A1c (HbA1c), plasma total cholesterol, triglycerides and non esterified fatty acid (NEFA). In particular, plasma triglyceride levels were reduced in the 0.6 % 5-campestenone-fed group to about 25 % of that in the control group. In the oral glucose tolerance test (OGTT) at three and seven weeks after the beginning of treatment, 5-campestenone limited the rise of blood glucose levels by oral administration of glucose dose-dependently. Amounts of adipose tissue in the retroperitoneum and periepididymal area as well as abdominal subcutaneous fat were significantly decreased in animals fed 0.6 % 5-campestenone. The blood leptin concentration on the final day of feeding was significantly in animals administered 5-campestenone. No obvious anomaly due to consumption of 5-campestenone was detected in necropsy or clinical observations.     

Beef cattle selected for increased muscularity have a reduced muscle response and increased adipose tissue response to adrenaline

The aim of this experiment was to evaluate the impact of selection for greater muscling on the adrenaline responsiveness of muscle, adipose and liver tissue, as reflected by changes in plasma levels of the intermediary metabolites lactate, non-esterified fatty acids (NEFA) and glucose. This study used 18-month-old steers from an Angus herd visually assessed and selected for divergence in muscling for over 15 years. Ten low muscled (Low), 11 high muscled (High) and 3 high muscled heterozygotes for myostatin mutation (High(Het)) steers were challenged with adrenaline doses ranging between 0.2 to 3.0 μg/kg live weight. For each challenge, 16 blood samples were taken between -30 and 130 min relative to adrenaline administration. Plasma was analysed for NEFA, lactate and glucose concentration and area under curve (AUC) over time was calculated to reflect the tissue responses to adrenaline. Sixteen basal plasma samples from each animal were also assayed for growth hormone. Muscle glycogen and lactate concentration were analysed from four muscle biopsies taken from the semimembranosus, semitendinosus and longissimus thoracis et lumborum of each animal at 14, 90 and 150 days on an ad libitum grain-based diet and at slaughter on day 157. In response to the adrenaline challenges, the High steers had 30% lower lactate AUC than the Low steers at challenges greater than 2 μg/kg live weight, indicating lower muscle responsiveness at the highest adrenaline doses. Aligning with this decrease in muscle response in the High animals were the muscle glycogen concentrations which were 6.1% higher in the High steers. These results suggest that selection for muscling could reduce the incidence of dark, firm, dry meat that is caused by low levels of glycogen at slaughter. At all levels of adrenaline challenge, the High steers had at least 30% greater NEFA AUC, indicating that their adipose tissue was more responsive to adrenaline, resulting in greater lipolysis. In agreement with this response, the High steers had a higher plasma growth hormone concentration, which is likely to have contributed to the increased lipolysis evident in these animals in response to adrenaline. This difference in lipolysis may in part explain the reduced fatness of muscular cattle. There was no effect of selection for muscling on liver responsiveness to adrenaline.     

ATGL and HSL are not coordinately regulated in response to fuel partitioning in fasted rats

Prolonged fasting is characterized by lipid mobilization (Phase 2), followed by protein breakdown (Phase 3). Knowing that body lipids are not exhausted in Phase 3, we investigated whether changes in the metabolic status of prolonged fasted rats are associated with differences in the expression of epididymal adipose tissue proteins involved in lipid mobilization. The final body mass, body lipid content, locomotor activity and metabolite and hormone plasma levels differed between groups. Compared with fed rats, adiposity and epididymal fat mass decreased in Phase 2 (approximately two- to threefold) and Phase 3 (∼4.5-14-fold). Plasma nonesterified fatty acids (NEFA) concentrations were increased in Phase 2 (approximately twofold) and decreased in Phase 3 (approximately twofold). Daily locomotor activity was markedly increased in Phase 3 (∼11-fold). Compared with the fed state, expressions of adipose triglyceride lipase (ATGL; mRNA and protein), hormone-sensitive lipase (HSL; mRNA) and phosphorylated HSL at residue Ser660 (HSL Ser⁶⁶⁰) were increased during Phase 2 (∼1.5-2-fold). HSL (mRNA and protein) and HSL Ser⁶⁶⁰ levels were lowered during Phase 3 (∼3-12-fold). Unlike HSL and HSL Ser⁶⁶⁰, ATGL expression did not correlate with circulating NEFA, mostly due to data from animals in Phase 3. At this stage, ATGL could play an essential role for maintaining a low mobilization rate of NEFA, possibly to sustain muscle performance and hence increased locomotor activity. We conclude that ATGL and HSL are not coordinately regulated in response to changes in fuel partitioning during prolonged food deprivation, ATGL appearing as the major lipase in late fasting.