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Perilipin is a lipid droplet surface protein present in adipocytes and steroidogenic cells. We examined five common single nucleotide polymorphisms (SNPs) at the perilipin ( PLIN) locus ( PLIN 6209C>T, 10171A>T, 11482G>A, 13041A>G, and 14995A>T) to investigate their association with obesity risk. The study population included 4,131 subjects of three ethnic groups (Chinese, Malay, and Indian) from Singapore. The prevalence of obesity in Malays and Indians was much higher than in Chinese. Moreover, in these groups the prevalence of obesity was three times higher in women than in men. Crude analysis indicated that haplotype 11212 (CAAAT) is shared by Malays and Indians and is significantly associated with increased obesity risk as compared to the most common haplotype 21111 (TAGAA): OR 1.65 (95% CI 1.11–2.46) in Malays and 1.94 (95% CI 1.06–3.53) in Indians. No associations between PLIN haplotypes and obesity risk were found in Chinese. To simplify the haplotype analyses we used a subgroup of three SNPs (11482G>A, 13041A>G, and 14995A>T) in positive linkage disequilibrium. These analyses revealed similar associations, showing that haplotypes XX212 (XXAAT) and XX222 (XXAGT) are associated with increased obesity risk in Malays OR 2.04 (95% CI 1.28–3.25) and 2.05 (95% CI 1.35–3.12) respectively, and that haplotype XXX212 (XXAAT) is significantly associated with increased obesity risk in Indians OR 2.16 (95% CI 1.10–4.26) after adjusting for covariates including age, sex, smoking, alcohol consumption, exercise, and diabetes status. Moreover, individual SNP analyses demonstrated that the PLIN 14995A>T SNP is the most informative single genetic marker for the observed haplotype association, being significantly associated with increased obesity risk in both Malays OR 2.28 (95% CI 1.45–3.57) and Indians OR 2.04 (95% CI 1.08–3.64). These results support the role of the PLIN locus as an ethnically dependent modulator of obesity risk in humans. [ABSTRACT FROM AUTHOR]

The relative contribution of circulating glucose to meal-to-meal variability in energy intake is not known. In 8 free-living young (median age 26.5 y) women with healthy body weight (median BMI 22.2 kg/m²), we measured glucose in the interstitial space by an automated monitoring procedure (continuous glucose monitoring system, CGMS™) for up to 3 consecutive days (mean 706 glucose readings per subject). We examined the association between interstitial glucose (which lags blood glucose by ∼10 min), self-reported hunger, satiety, desire for a meal, and nutrient intakes. Participants reported consuming a typical Western diet (59% carbohydrate, 27% fat, 14% protein). Median (interquartile range) interstitial glucose was 5.2 mmol/L (4.7–5.8). Using repeated- measures techniques in univariate analyses, desire for a meal (r = 0.45, P < 0.0001), hunger (r = 0.37, P = 0.0002), satiety (r = -0.40, P < 0.0001), low interstitial absolute mean glucose up to 25 min before eating (r = -0.23, P = 0.02), and a large decline in glucose between 40 and 5 mm before eating (r = -0.17, P = 0.08) were all associated with meal energy intake. In multivariate regression analyses, desire for a meal (P < 0.0001) and hunger (P = 0.02) were the strongest independent contributors to meal energy intake, whereas absolute mean glucose measured in the period 15 to 0 mm before eating was marginally significant (P = 0.08). In conclusion, absolute glucose level is a significant predictor of energy intake in nonobese women. However, desire for a meal and hunger are quantitatively more important, emphasizing the importance of both glucose signals and nonglucose (internal or environmental) factors in within-subject variability in energy intake. In addition, the CGMS may have utility in understanding the role of circulating glucose in energy regulation in free-living subjects under a wide range of different nutritional conditions. [ABSTRACT FROM AUTHOR]

Perilipin (Peri) A is a lipid droplet-associated phosphoprotein that acts dually as a suppressor of basal (constitutive) lipolysis and as an enhancer of cyclic AMPdependent protein kinase (PKA)-stimulated lipolysis by both hormone-sensitive lipase (HSL) and non-HSL(s). To identify domains of Peri A that mediate these multiple actions, we introduced adenoviruses expressing truncated or mutated Peri A and HSL into NIH 3T3 fibroblasts lacking endogenous perilipins and HSL but overexpressing acyl-CoA synthetase 1 and fatty acid transporter 1. We identified two lipase-selective functional domains: 1) Peri A (amino acids 1-300), which inhibits basal lipolysis and promotes PKA-stimulated lipolysis by HSL, and 2) Peri A (amino acids 301-517), which inhibits basal lipolysis by non-HSL and promotes PKA-stimulated lipolysis by both HSL and non-HSL. PKA site mutagenesis revealed that PKA-stimulated lipolysis by HSL requires phosphorylation of one or more sites within Peri 1-300 (Ser[sup 81], Ser[sup 222], and Ser[sup 276]). PKAstimulated lipolysis by non-HSL additionally requires phosphorylation of one or more PKA sites within Peri 301-517 (Ser[sup 433], Ser[sup 492], and Ser[sup 517]). Peri 301-517 prorooted PKA-stimulated lipolysis by HSL yet did not block HSL-mediated basal lipolysis, indicating that an additional region(s) within Peri 301-517 promotes hormone-stimulated lipolysis by HSL. These results suggest a model of Peri A function in which 1) lipase-specific "barrier" domains block basal lipolysis by HSL and nonHSL, 2) differential PKA site phosphorylation allows PKA-stimulated lipolysis by HSL and non-HSL, respectively, and 3) additional domains within Peri A further facilitate PKA-stimulated lipolysis, again with lipase selectivity. [ABSTRACT FROM AUTHOR]

Little is known about the relative effects of fermentable fiber (FF) vs. nonfermentable fiber (NFF) on energy regulation in humans. We compared 27 +/- 0.6 g/d supplements of FF (pectin, beta-glucan) and NFF (methylcellulose) for their ability to decrease ad libitum energy intake (EI) and hunger, increase satiety and cause spontaneous body weight and fat losses. Men and women (n = 11) aged 23-46 y, BMI 20.0-34.4 kg/m2, consumed first NFF and then FF for 3 wk each, with a 4-wk washout period between phases. Daily satiety assessed with analog scales was higher with NFF than FF (60.7 +/- 1.0 vs. 57.7 +/- 0.8 mm, P = 0.01). However, there were no differences in reported EI (NFF < FF by 7%, P = 0.31, NFF < baseline by 9.5%, P = 0.11), body weight (NFF 0.13 kg, P = 0.73; FF 0.13 kg, P = 0.60) or fat percentage (NFF -0.3%, P = 0.56; FF -0.1%, P = 0.66) within either phase. In contrast to findings in animals, NFF was more, rather than less satiating than FF, and use of neither NFF nor FF preparations was associated with body weight or fat loss. These pilot results suggest no role for short-term use of FF and NFF supplements in promoting weight loss in humans consuming a diet ad libitum. [ABSTRACT FROM AUTHOR]

We used clinically relevant murine allogeneic bone marrow transplantation (BMT) models to study the mechanisms by which IL-7 administration can improve posttransplant peripheral T cell reconstitution. After transplant we could distinguish two populations of mature donor T cells: (a) alloreactive T cells with decreased expression of CD127 (IL-7 receptor alpha chain) and (b) nonalloreactive T cells, which express CD127 and undergo homeostatic proliferation. IL-7 administration increased the homeostatic proliferation of nonalloreactive T cells, but had no effect on alloreactive T cells and the development of graft-versus-host disease. Allogeneic transplant of purified hematopoietic stem cells and adoptive transfer of thymocytes into lethally irradiated hosts suggested that recent thymic emigrants can undergo homeostatic proliferation and acquire a memory-like phenotype. We found by BrdU pulse-chase, cell cycle, and annexin V analyses that IL-7 administration has significant proliferative and antiapoptotic effects on posttransplant peripheral T cells. We conclude that homeostatic expansion is important for T cell reconstitution after allogeneic BMT and involves both transferred mature T cells and recent thymic emigrants. Apart from its thymopoietic effects, IL-7 promotes peripheral T cell reconstitution through its selective proliferative and antiapoptotic effects on nonalloreactive and de novo-generated T cells, but has no effect on alloreactive T cells. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that exhibits specific tumoricidal activity against a variety of tumors. It is expressed on different cells of the immune system and plays a role in natural killer cell–mediated tumor surveillance. In allogeneic hematopoietic-cell transplantation, the reactivity of the donor T cell against malignant cells is essential for the graft-versus-tumor (GVT) effect. Cytolytic activity of T cells is primarily mediated through the Fas–Fas ligand and perforin–granzyme pathways. However, T cells deficient for both Fas ligand and perforin can still exert GVT activity in vivo in mouse models. To uncover a potential role for TRAIL in donor T cell–mediated GVT activity, we compared donor T cells from TRAIL-deficient and wild-type mice in clinically relevant mouse bone-marrow transplantation models. We found that alloreactive T cells can express TRAIL, but the absence of TRAIL had no effect on their proliferative and cytokine response to alloantigens. TRAIL-deficient T cells showed significantly lower GVT activity than did TRAIL-expressing T cells, but no important differences in graft-versus-host disease, a major complication of allogeneic hematopoietic cell transplantation, were observed. These data suggest that strategies to enhance TRAIL-mediated GVT activity could decrease relapse rates of malignancies after hematopoietic cell transplantation without exacerbation of graft-versus-host disease. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-alpha (TNF-alpha) stimulates lipolysis in human adipocytes. However, the mechanisms regulating this process are largely unknown. We demonstrate that TNF-alpha increases lipolysis in differentiated human adipocytes by activation of mitogen-activated protein kinase kinase (MEK), extracellular signal-related kinase (ERK), and elevation of intracellular cAMP. TNF-alpha activated ERK and increased lipolysis; these effects were inhibited by two specific MEK inhibitors, PD98059 and U0126. TNF-alpha treatment caused an electrophoretic shift of perilipin from 65 to 67 kDa, consistent with perilipin hyperphosphorylation by activated cAMP-dependent protein kinase A (PKA). Coincubation with TNF-alpha and MEK inhibitors caused perilipin to migrate as a single 65-kDa band. Consistent with the hypothesis that TNF-alpha induces perilipin hyperphosphorylation by activating PKA, TNF-alpha increased intracellular cAMP approximately 1.7-fold, and the increase was abrogated by PD98059. Furthermore, H89, a specific PKA inhibitor, blocked TNF-alpha-induced lipolysis and the electrophoretic shift of perilipin, suggesting a role for PKA in TNF-alpha-induced lipolysis. Finally, TNF-alpha decreased the expression of cyclic-nucleotide phosphodiesterase 3B (PDE3B) by approximately 50%, delineating a mechanism by which TNF-alpha could increase intracellular cAMP. Cotreatment with PD98059 restored PDE3B expression. These studies suggest that in human adipocytes, TNF-alpha stimulates lipolysis through activation of MEK-ERK and subsequent increase in intracellular cAMP. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α (TNF-α) stimulates lipolysis in human adipocytes. However, the mechanisms regulating this process are largely unknown. We demonstrate that TNF-α increases lipolysis in differentiated human adipocytes by activation of mitogen-activated protein kinase (MEK), extracellular signal-related kinase (ERK), and elevation of intracellular cAMP. TNF-α activated ERK and increased lipolysis; these effects were inhibited by two specific MEK inhibitors, PD98059 and U0126. TNF-α treatment caused an electrophoretic shift of perilipin from 65 to 67 kDa, consistent with perilipin hyperphosphorylation by activated cAMP dependent protein kinase A (PKA). Coincubation with TNF-α and MEK inhibitors caused perilipin to migrate as a single 65-kDa band. Consistent with the hypothesis that TNF-α induces perilipin hyperphosphorylation by activating PKA, TNF-α increased intracellular cAMP ∼l.7-fold, and the increase was abrogated by PD98059. Furthermore, H89, a specific PKA inhibitor, blocked TNF-α-induced lipolysis and the electrophoretic shift of perilipin, suggesting a role for PKA in TNF-α-induced lipolysis. Finally, TNF-α decreased the expression of cyclic-nucleotide phosphodiesterase 3B (PDE3B) by ∼50%, delineating a mechanism by which TNF-α could increase intracellular cAMP. Cotreatment with PD98059 restored PDE3B expression. These studies suggest that in human adipocytes, TNF-α stimulates lipolysis through activation of MEK-ERK and subsequent increase in intracellular cAMP. [ABSTRACT FROM AUTHOR]

Investigates the effects of peroxisome proliferator-activated receptor(PPAR)-γ agonists and PPARα agonist on HIV replication and tumor necrosis factor (TNF)α production in peripheral blood mononuclear cells. Inhibition of cell replication; Absence of correlation of TNFα inhibition with the quantitative decrease in HIV replication.

HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been linked to the development of a metabolic syndrome in which adipocyte insulin resistance appears to play a major role. In this study, we assessed the effect of nelfinavir on glucose uptake and lipolysis in differentiated 3T3-L1 adipocytes. An 18-h exposure to nelfinavir resulted in an impaired insulin-stimulated glucose uptake and activation of basal lipolysis. Impaired insulin stimulation of glucose up take occurred at nelfinavir concentrations >10 micromol/l (EC(50) = 20 micromol/l) and could be attributed to impaired GLUT4 translocation. Basal glycerol and free fatty acid (FFA) release were significantly enhanced with as low as 5 micromol/l nelfinavir, displaying fivefold stimulation of FFA release at 10 micromol/l. Yet, the antilipolytic action of insulin was preserved at this concentration. Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin. Troglitazone pre- and cotreatment with nelfinavir partly protected the cells from the increase in basal lipolysis, but it had no effect on the impairment in insulin-stimulated glucose uptake induced by this HPI. This study demonstrates that nelfinavir induces insulin resistance and activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte metabolism in treated HIV patients. [ABSTRACT FROM AUTHOR]

The effect of aging on energy regulation remains controversial. We compared the effects of underfeeding on changes in energy expenditure and respiratory quotient in young normal weight men and women [YNW, age 25.7 +/- 3.2 y(SD), body mass index (BMI) 23.1 +/- 1.6 kg/m(2)], young overweight men and women (YOW, age 26.1 +/- 3.5 y, BMI 27.7 +/- 2.1 kg/m(2)) and older (OLD) men and women (age 68.4 +/- 3.3 y, BMI 27.4 +/- 3.4 kg/m(2)). The thermic effect of feeding (TEF) during weight maintenance, and changes in resting energy expenditure (REE) and respiratory quotient were determined in response to undereating by an average 3.75 MJ/d for 6 wk. In addition, body composition was measured. No significant differences among the groups were observed in TEF, fasting and postprandial respiratory quotient, or the change in fasting respiratory quotient with underfeeding. However, REE adjusted for fat-free mass and fat mass was significantly lower in OLD subjects compared with YNW and YOW subjects (P < 0.05). In addition, the REE response to weight change was significantly attenuated in the OLD subjects (P = 0.023). These data suggest that the responsiveness of energy expenditure to negative energy balance is attenuated in old age, and provide further support for the hypothesis that mechanisms of energy regulation are broadly disregulated in old age. [ABSTRACT FROM AUTHOR]

Hypertension, dyslipidemia and overweight contribute substantially to cardiovascular disease risk. One of the most effective methods for improving high blood pressure and lipid profiles is loss of excess weight. Other recommendations for reducing cardiovascular risk include changes in dietary micronutrient, macronutrient and fiber intakes. To better define a diet for reduction in cardiovascular risk, 43 adults (body mass index 26.4 +/- 3.3, range 20.5-33.9 kg/m(2)) participated in an 8-wk study to determine the effects of two diets on weight, blood pressure, lipids and insulin sensitivity. For 2 wk, weight was maintained and all subjects consumed a control diet. For the next 6 wk, subjects consumed one of two hypocaloric diets (maintenance energy minus 4.2 MJ/d): the control diet (n = 21) or a diet containing oats [45 g/(4.2 MJ dietary energy. d), n = 22]. There was no significant difference between groups in changes in weight loss (control -4.0 +/- 1.1 kg, oats -3.9 +/- 1.6 kg, P = 0.8). The oats diet resulted in greater decreases in mean systolic blood pressure (oats -6 +/- 7 mm Hg, control -1 +/- 10 mm Hg, P = 0.026), whereas diastolic blood pressure change did not differ between the two groups (oats -4 +/- 6 mm Hg, control -3 +/- 5 mm Hg, P = 0.8). The oat diet resulted in significantly greater decreases in total cholesterol (oats -0.87 +/- 0.47 mmol/L, control -0.34 +/- 0.5 mmol/L, P = 0.003) and LDL cholesterol (oats -0.6 +/- 0.41 mmol/L, control -0.2 +/- 0.41mmol/L, P = 0.008). In summary, a hypocaloric diet containing oats consumed over 6 wk resulted in greater improvements in systolic blood pressure and lipid profile than did a hypocaloric diet without oats. [ABSTRACT FROM AUTHOR]

Background: Dietary restraint, a term used to describe the intentional control of food intake to prevent weight gain or promote weight loss, is commonly practiced by older adults, but little is known about its effects on physiology and metabolism.Methods: We therefore compared a wide range of parameters between groups of healthy non-obese postmenopausal women classified psychometrically as unrestrained eaters (body mass index [BMI] 23.8 +/- 0.6 [SEM] kg/m(2), n = 28) or restrained eaters (BMI 24.5 +/- 0.5, n = 39). Measurements were made of reported micronutrient intakes, cardiopulmonary function, hematology, body temperature, skin thickness, bone mass, and immune function; in addition, self-perceived health, mood, and some dimensions of eating behavior were assessed by questionnaire.Results: Macronutrient and micronutrient intakes were not significantly different between restrained and unrestrained eaters reporting energy intake to within 30% of predicted total energy expenditure. Restrained eaters had significantly lower hemoglobin (12.9 +/- 0.1 [SEM] vs 13.2 +/- 0.1 g/dl; p <.05), but values were within the normal range in both groups. In addition, restrained eaters scored significantly higher on the Eating Attitudes Test (p <.01) and drive-for-thinness (p <.001) and maturity fears (p <.05) subscores of the Eating Disorders Inventory, but values were again within the normal range. No other parameter differed significantly between groups.Conclusions: In this normal-weight population, restrained eating was not associated with detrimental effects in a wide range of physiological, metabolic, and health characteristics. Further work is needed to determine the relevance of these results to the general population. [ABSTRACT FROM AUTHOR]

Recent studies have suggested a short-term impairment in the regulation of food intake in older adults, but further studies are needed to determine if a longer-term impairment exists and to identify underlying causes. Changes in body weight and composition were measured over a 6-week underfeeding study and a 6-month follow-up period in healthy young (n = 23) and older (OLD, n = 18) men and women. The young adults were either normal weight (YNW, n = 12) or overweight (YOW, n = 11). Energy intakes during underfeeding were 896 +/- 18 (SEM) kcal less than weight-maintenance energy requirements determined prior to underfeeding. In addition, changes in perceived hunger during underfeeding were monitored in a subgroup (n = 19). OLD and YOW subjects lost significantly more weight during underfeeding than did YNW subjects (p = .025 and .000, respectively), and they did not gain back significant weight in the 6-month follow-up. In addition, OLD subjects reported a significantly lower frequency of hunger during underfeeding (p = .05). There was no significant difference among groups in the relationship between weight lost and fat-free mass lost. Healthy OLD adults have an impaired ability to regulate food intake over at least 6 months following underfeeding compared with YNW adults, and a reduction in their perceived frequency of hunger may be a contributing factor. [ABSTRACT FROM AUTHOR]

An imbalance in the storage and breakdown of hepatic lipid droplet (LD) triglyceride (TAG) leads to hepatic steatosis, a defining feature of non-alcoholic fatty liver disease (NAFLD). The two primary cellular pathways regulating hepatic TAG catabolism are lipolysis, initiated by adipose triglyceride lipase (ATGL), and lipophagy. Each of these processes requires access to the LD surface to initiate LD TAG catabolism. Ablation of perilipin 2 (PLIN2), the most abundant lipid droplet-associated protein in steatotic liver, protects mice from diet-induced NAFLD. However, the mechanisms underlaying this protection are unclear. We tested the contributions of ATGL and lipophagy mediated lipolysis to reduced hepatic TAG in mice with liver-specific PLIN2 deficiency (PLIN2LKO) fed a Western-type diet for 12 weeks. We observed enhanced autophagy in the absence of PLIN2, as determined by ex vivo p62 flux, as well as increased p62- and LC3-positive autophagic vesicles in PLIN2LKO livers and isolated primary hepatocytes. Increased levels of autophagy correlated with significant increases in cellular fatty acid (FA) oxidation in PLIN2LKO hepatocytes. We observed that inhibition of either autophagy or ATGL blunted the increased FA oxidation in PLIN2LKO hepatocytes. Additionally, combined inhibition of ATGL and autophagy reduced FA oxidation to the same extent as treatment with either inhibitor alone. In sum, these studies show that protection against NAFLD in the absence of hepatic PLIN2 is driven by the integrated actions of both ATGL and lipophagy. [ABSTRACT FROM AUTHOR]

Thiazolidinediones (TZDs) such as BRL 49653 are a class of antidiabetic agents that are agonists for the peroxisome proliferator-activated nuclear receptor (PPAR-gamma2). In vivo, TZDs reduce circulating levels of free fatty acids (FFAs) and ameliorate insulin resistance in individuals with obesity and NIDDM. Adipocyte production of TNF-alpha is proposed to play a role in the development of insulin resistance, and because BRL 49653 has been shown to antagonize some of the effects of TNF-alpha, we examined the effects of TNF-alpha and BRL 49653 on adipocyte lipolysis. After a 24-h incubation of TNF-alpha (10 ng/ml) with 3T3-L1 adipocytes, glycerol release increased by approximately 7-fold, and FFA release increased by approximately 44-fold. BRL 49653 (10 pmol/l) reduced TNF-alpha-induced glycerol release by approximately 50% (P < 0.001) and FFA release by approximately 90% (P < 0.001). BRL 49653 also reduced glycerol release by approximately 50% in adipocytes pretreated for 24 h with TNF-alpha. Prolonged treatment (5 days) with either BRL 49653 or another PPAR-gamma2 agonist, 15-d delta-12,14-prostaglandin J2 (15-d deltaPGJ2), blocked TNF-alpha-induced glycerol release by approximately 100%. Catecholamine (isoproterenol)-stimulated lipolysis was unaffected by BRL 49653 and 15-d deltaPGJ2. BRL 49653 partially blocked the TNF-alpha-mediated reduction in protein levels of hormone-sensitive lipase and perilipin A, two proteins involved in adipocyte lipolysis. These data suggest a novel pathway that may contribute to the ability of the TZDs to reduce serum FFA and increase insulin sensitivity. [ABSTRACT FROM AUTHOR]

Abstract: Menopause, the age-related loss of ovarian hormone production, promotes increased adiposity and associated metabolic pathology, but molecular mechanisms remain unclear. We previously reported that estrogen increases skeletal muscle PPARδ expression in vivo, and transgenic mice overexpressing muscle-specific PPARδ are reportedly protected from diet-induced obesity. We thus hypothesized that obesity observed in ovariectomized mice, a model of menopause, may result in part from abrogated expression of muscle PPARδ and/or downstream mediators such as FoxO1. To test this hypothesis, we ovariectomized (OVX) or sham-ovariectomized (SHM) 10-week old female C57Bl/6J mice, and subsequently harvested quadriceps muscles 12weeks later for gene expression studies. Compared to SHM, muscle from OVX mice displayed significantly decreased expression of PPARδ (3.4-fold), FoxO1 (4.5-fold), PDK-4 (2.3-fold), and UCP-2 (1.8-fold). Consistent with studies indicating PPARδ and FoxO1 regulate muscle fiber type, we observed dramatic OVX-specific decreases in slow isoforms of the contractile proteins myosin light chain (11.1-fold) and troponin C (11.8-fold). In addition, muscles from OVX mice expressed 57% less myogenin (drives type I fiber formation), 2-fold more MyoD (drives type II fiber formation), and 1.6-fold less musclin (produced exclusively by type II fibers) than SHM, collectively suggesting a shift towards less type I oxidative fibers. Finally, and consistent with changes in PPARδ and FoxO1 activity, we observed decreased expression of atrogin-1 (2.3-fold) and MuRF-1 (1.9-fold) in OVX mice. In conclusion, muscles from ovariectomized mice display decreased PPARδ and FoxO1 expression, abrogated expression of downstream targets involved in lipid and protein metabolism, and gene expression profiles indicating less type I oxidative fibers. [Copyright &y& Elsevier]

This article discusses research being done on the use of amylopectin starch in promoting the development of insulin resistance. It references a study by S. E. Byrnes et al published in a 1995 issue of the Journal of Nutrition. It compares the effect of a low-glycemic load hypocaloric diet and high-glycemic load diet on healthy overweight men and women.

Activation of the fuel-sensing enzyme AMPK has been shown to improve various conditions associated with obesity and type 2 diabetes. In adipocytes, beta-adrenergic agonists activate AMPK; however the mechanism(s) by which they do so is not known. In the present study we examined whether the effect of these agents is dependent on their ability to stimulate lipolysis. Incubation of 3T3-L1 adipocytes with isoproterenol, isobutylmethylxanthine or forskolin increased AMPK activity, as reflected by a 3-fold increase in P-ACC Ser79 and a 2-fold increase in P-AMPK T172-within 1 hour. ShRNA-mediated silencing of adipose tissue triglyceride lipase (ATGL), a key regulator of triglyceride hydrolysis, totally inhibited the stimulation of both lipolysis and AMPK activation by forskolin. Likewise, co-incubation of the adipocytes with the general lipase inhibitor orlistat caused a 50% inhibition of both forskolin-stimulated lipolysis and AMPK activation. In contrast, orlistat did not diminish forskolin-induced increases in the abundance of P-CREB Ser 133 or P-LKB1 Ser431, indicating that it did not alter signaling events caused by PKA activation. We then assessed whether a change in cellular energy state (AMP/ATP ratio) mediated the activation of AMPK caused by lipolysis. In support of this notion, incubation with forskolin caused a 4-fold increase in the cellular AMP/ATP ratio. Conversely, when forskolin stimulated-lipolysis was partially inhibited by orlistat, both the activation of AMPK, and the increase in the AMP/ATP ratio were diminished by 50%. Fatty acyl CoA synthase (ACS) uses ATP and generates AMP when it catalyzes the conversion of flee fatty acids to fatty acyl CoA. When We inhibited ACS with triacsin C, activation of AMPK by forskolin was completely abrogated despite the fact that lipolysis was increased to the same extent as in control conditions. In conclusion, the results indicate that the activation of AMPK following beta-adrenergic stimulation of the adipocyte is secondary to lipolysis and is not the direct result of increases in cAMP abundance or PKA activity. They suggest that a decrease in energy state most likely explains how lipolysis activates AMPK and that the energy-consuming enzyme ACS is involved in this mechanism. [ABSTRACT FROM AUTHOR]