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Exogenous dietary fat can induce obesity and promote diabetes, but endogenous fat production is not thought to affect skeletal muscle insulin resistance, an antecedent of metabolic disease. Unexpectedly, the lipogenic [...]

Mechanisms controlling the proliferative activity of neural stem and progenitor cells (NSPCs) have a pivotal role to ensure life-long neurogenesis in the mammalian brain (1). How metabolic programs are coupled [...]

After loss of intestinal surface area, the remaining bowel undergoes a morphometric and functional adaptive response. Enterocytic expression of the transcriptional coregulator tetradecanoyl phorbol acetate induced sequence 7 (Tis7) is markedly increased in a murine model of intestinal adaptation. Mice overexpressing Tis7 in intestine have greater triglyceride absorption and weight gain when fed a high-fat diet (42% energy) than their wild-type (WT) littermates fed the same diet. These and other data suggest that Tis7 has a unique role in nutrient absorptive and metabolic adaptation. Herein, male [Tis7.sup.-/-] and WT mice were fed a high-fat diet (42% energy) for 8 wk. Weight was monitored and metabolic analyses and hepatic and intestinal lipid concentrations were compared after 8 wk. Intestinal lipid absorption and metabolism studies and intestinal resection surgeries were performed in separate groups of [Tis7.sup.-/-] and WT mice. At 8 wk, weight gain was less and jejunal mucosal and hepatic triglyceride and cholesterol concentrations were lower in [Tis7.sup.-/-] mice than in the WT controls. Following corn oil gavage, serum cholesterol, triglyceride, and FFA concentrations were lower in the [Tis7.sup.-/-] mice than in the WT mice. Incorporation of oral [sup.3][H] triolein into intestinal mucosal cholesterol ester and FFA was less in [Tis7.sup.-/-] compared with WT mice. Following resection, crypt cell proliferation rates and villus heights were lower in [Tis7.sup.-/-] than in VVT mice, indicating a blunted adaptive response. Our results suggest a novel physiologic function for Tis7 in the gut as a global regulator of lipid absorption and metabolism and epithelial cell proliferation. J. Nutr. 140: 1907-1914, 2010. doi: 10.3945/jn.110.127084.

Phospholipases [A.sub.2] ([PLA.sub.2]) play important roles in metabolic processes, and the Group VI [PLA.sub.2] family is comprised of intracellular enzymes that do not require [Ca.sup.2+] for catalysis. Mice deficient in Group VIA [PLA.sub.2] ([iPLA.sub.2][beta]) develop more severe glucose intolerance than wild-type (WT) mice in response to dietary stress. Group VIB [PLA.sub.2] ([iPLA.sub.2][gamma]) is a related enzyme distributed in membranous organelles, including mitochondria, and [iPLA.sub.2][gamma] knockout (KO) mice exhibit altered mitochondrial morphology and function. We have compared metabolic responses of [iPLA.sub.2][gamma]-KO and WT mice fed a Western diet (WD) with a high fat content. We find that KO mice are resistant to WD-induced increases in body weight and adiposity and in blood levels of cholesterol, glucose, and insulin, even though WT and KO mice exhibit similar food consumption and dietary fat digestion and absorption. KO mice are also relatively resistant to WD-induced insulin resistance, glucose intolerance, and altered patterns of fat vs. carbohydrate fuel utilization. KO skeletal muscle exhibits impaired mitochondrial [beta]-oxidation of fatty acids, as reflected by accumulation of larger amounts of long-chain acylcarnitine (LCAC) species in KO muscle and liver compared with WT in response to WD feeding. This is associated with increased urinary excretion of LCAC and much reduced deposition of triacylglycerols in liver by WD-fed KO compared with WT mice. The iPLA2[gamma]-deficient genotype thus results in a phenotype characterized by impaired mitochondrial oxidation of fatty acids and relative resistance to the metabolic abnormalities induced by WD. insulin resistance; glucose intolerance; diabetes; lipids; mass spectrometry doi: 10.1152/ajpendo.00780.2009.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.05.036 Byline: Manu V. Chakravarthy (1), Irfan J. Lodhi (1), Li Yin (1), Raghu R.V. Malapaka (3), H. Eric Xu (3), John Turk (1), Clay F. Semenkovich (1)(2) Keywords: PROTEINS; SIGNALING; HUMDISEASE Abstract: The nuclear receptor PPAR[alpha] is activated by drugs to treat human disorders of lipid metabolism. Its endogenous ligand is unknown. PPAR[alpha]-dependent gene expression is impaired with inactivation of fatty acid synthase (FAS), suggesting that FAS is involved in generation of a PPAR[alpha] ligand. Here we demonstrate the FAS-dependent presence of a phospholipid bound to PPAR[alpha] isolated from mouse liver. Binding was increased under conditions that induce FAS activity and displaced by systemic injection of a PPAR[alpha] agonist. Mass spectrometry identified the species as 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Knockdown of Cept1, required for phosphatidylcholine synthesis, suppressed PPAR[alpha]-dependent gene expression. Interaction of 16:0/18:1-GPC with the PPAR[alpha] ligand-binding domain and coactivator peptide motifs was comparable to PPAR[alpha] agonists, but interactions with PPAR[delta] were weak and none were detected with PPAR[gamma]. Portal vein infusion of 16:0/18:1-GPC induced PPAR[alpha]-dependent gene expression and decreased hepatic steatosis. These data suggest that 16:0/18:1-GPC is a physiologically relevant endogenous PPAR[alpha] ligand. Author Affiliation: (1) Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, USA (2) Department of Cell Biology and Physiology, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, USA (3) Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA Article History: Received 29 August 2008; Revised 10 March 2009; Accepted 7 May 2009 Article Note: (miscellaneous) Published online: July 30, 2009

Niemann-Pick C1 (NPC1) is a key participant in cellular cholesterol trafficking. Loss of NPC1 function leads to defective suppression of SREBP-dependent gene expression and failure to appropriately activate liver X receptor--mediated (LXR-mediated) pathways, ultimately resulting in intracellular cholesterol accumulation. To determine whether NPC1 contributes to regulation of macrophage sterol homeostasis in vivo, we examined the effect of NPC1 deletion in BM-derived cells on atherosclerotic lesion development in the Ldlr-/- mouse model of atherosclerosis. High-fat diet--fed chimeric Npc1-/- mice reconstituted with Ldlr-/-Npc1-/- macrophages exhibited accelerated atherosclerosis despite lower serum cholesterol compared with mice reconstituted with wild-type macrophages. The discordance between the low serum lipoprotein levels and the presence of aortic atherosclerosis suggested that intrinsic alterations in macrophage sterol metabolism in the chimeric Npc1-/- mice played a greater role in atherosclerotic lesion formation than did serum lipoprotein levels. Macrophages from chimeric Npc1-/- mice showed decreased synthesis of 27-hydroxycholesterol (27-HC), an endogenous LXR ligand; decreased expression of LXR-regulated cholesterol transporters; and impaired cholesterol efflux. Lower 27-HC levels were associated with elevated cholesterol oxidation products in macrophages and plasma of chimeric Npc1-/- mice and with increased oxidative stress. Our results demonstrate that NPC1 serves an atheroprotective role in mice through regulation of LXR-dependent cholesterol efflux and mitigation of cholesterol-induced oxidative stress in macrophages., Introduction Macrophages regulate tissue lipid homeostasis through the uptake and catabolism of atherogenic plasma lipoproteins (1). Macrophages express scavenger receptor A and CD36, which bind and internalize modified lipoproteins, such [...]

Nonstandard abbreviations used: ACO, acyl-CoA oxidase; AgRP, agouti-related protein; CART, cocaine-amphetamine- related transcript; CPT-1, carnitine palmitoyltransferase-1; FAS, fatty acid synthase; FASKO mice, mice lacking FAS in pancreatic p" cells and [...]

Fibrates, activators of the nuclear receptor PPAR[alpha], improve dyslipidemia, but their effects on insulin resistance and vascular disease are unresolved. To test the hypothesis that PPAR[alpha] activation improves insulin resistance and vascular function, we determined the effects of fenofibrate in healthy adults with insulin resistance induced by short-term glucocorticoid administration. Eighteen normal-weight subjects were studied in four stages: at baseline, after 21 days of fenofibrate (160 mg/day) alone, after 3 days of dexamethasone (8 mg/day) added to fenofibrate, and after 3 days of dexamethasone added to placebo (dexamethasone alone). Dexamethasone alone caused hyperinsulinemia, increased glucose, decreased glucose disposal, and reduced insulin-induced suppression of hepatic glucose production as determined by hyperinsulinemic euglycemic clamp and increased systolic blood pressure as determined by ambulatory monitoring, features associated with an insulin-resistant state. Fenofibrate improved fasting LDL and total cholesterol in the setting of dexamethasone treatment but had no significant effect on levels of insulin or glucose, insulin-stimulated glucose disposal, or insulin suppression of glucose production during clamps, or ambulatory monitored blood pressure. In the absence of dexamethasone, fenofibrate lowered fasting triglycerides and cholesterol but unexpectedly increased systolic blood pressure by ambulatory monitoring. These data suggest that PPAR[alpha] activation in humans does not correct insulin resistance induced by glucocorticoids and may adversely affect blood pressure. peroxisome proliferator-activated receptor-[alpha]; dexamethasone; insulin sensitivity; metabolic syndrome

Considerable evidence supports the association between insulin resistance and vascular disease, and this has led to wide acceptance of the clustering of hyperlipidemia, glucose intolerance, hypertension, and obesity as a [...]

Author(s): Carlos Bernal-Mizrachi [1, 4]; Allison C. Gates [1, 4]; Sherry Weng [1]; Takuji Imamura [2]; Russell H. Knutsen [3]; Pascual DeSantis [1]; Trey Coleman [1]; R. Reid Townsend [1]; [...]

To address the potential role of lipotoxicity and mitochondrial function in insulin resistance, we studied mice with high-level expression of uncoupling protein-I in skeletal muscle (UCP-H mice). Body weight, body length, and bone mineral density were decreased in UCP-H mice compared with wild-type littermates. Forelimb grip strength and muscle mass were strikingly decreased, whereas muscle triglyceride content was increased fivefold in UCP-H mice. Electron microscopy demonstrated lipid accumulation and large mitochondria with abnormal architecture in UCP-H skeletal muscle. ATP content and key mitochondrial proteins were decreased in UCP-H muscle. Despite mitochondrial dysfunction and increased intramyocellular fat, fasting serum glucose was 22% lower and insulin-stimulated glucose transport 80% higher in UCP-H animals. These beneficial effects on glucose metabolism were associated with increased AMP kinase and hexokinase activities, as well as elevated levels of GLUT4 and myocyte enhancer factor-2 proteins A and D in skeletal muscle. These results suggest that UCP-H mice have a mitochondrial myopathy due to depleted energy stores sufficient to compromise growth and impair muscle function. Enhanced skeletal muscle glucose transport in this setting suggests that excess intramyocellular lipid and mitochondrial dysfunction are not sufficient to cause insulin resistance in mice, uncoupling protein; insulin resistance; lipotoxicity; mitochondria

Protease inhibitor-based highly active antiretroviral therapy (PI-HAART) has been implicated in dyslipidemia, peripheral insulin resistance, and abnormal adipose tissue deposition in human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome, or AIDS. In vitro evidence indicates that some PIs reduce adipocyte lipoprotein (LPL) and hepatic lipase (HL) expression and activities. We examined whether LPL and HL activities are reduced in HIV-infected patients with dyslipidemia. Fasting serum lipids, glucoregulatory hormones, and postheparin LPL and HL activities, as well as whole body and regional adiposity, were measured in 19 HIV-seronegative controls, 9 HIV+ patients naive to all anti-HIV medications, 9 HIV+ patients naive to PIs, 9 HIV+ patients with prior PI experience but not currently receiving PIs, and 47 HIV+ patients receiving PI-HAA T. The PIHAART group had low LPL and HL activities. However, multiple linear regression analysis indicated that low postheparin LPL activity contributed only partially to HIV-dyslipidemia. Central adiposity and high C-peptide levels (an indicator of high insulin secretion) were stronger predictors of HIV-dyslipidemia. Low LPL and HL activities, by themselves, were insufficient to explain HIV-dyslipidemia because the PI-naive group had low LPL and HL activities but had normal adiposity, C-peptide levels, and serum lipid and lipoprotein levels. HDL-cholesterol was lower in PI-HAART and PI-naive groups than seronegative controls and was directly associated with LPL activity. These findings suggest that HIV-dyslipidemia is mediated primarily by factors that influence triglyceride and lipoprotein synthesis (e.g., central adiposity and hyperinsulinemia) and mediated only partially by factors that influence triglyceride clearance (e.g., lipase activity). acquired immunodeficiency syndrome; human immunodeficiency virus; metabolic complications; insulin resistance; central obesity; aspartyl protease inhibitors; lipoprotein lipase; magnetic resonance imaging

Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator-activated receptor-[alpha] (PPAR-[alpha]) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr[sup.-/-]), with (Ppara[sup.+/+]) or without (Ppara[sup.-/-]) PPAR-[alpha], were treated chronically with dexamethasone. Ppara[sup.+/+], but not Ppara[sup.-/-], mice developed hyperglycemia, hyperinsulinemia and hypertension. Similar effects on glucose metabolism were seen in a different model using C57BL/6 mice. Hepatic gluconeogenic gene expression was increased and insulin-mediated suppression of endogenous glucose production was less effective in dexamethasone-treated Ppara[sup.+/+] mice. Adenoviral reconstitution of PPAR-[alpha] in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara[sup.-/-] mice induced hyperglycemia, hyperinsulinemia and increased gluconeogenic gene expression. It also increased blood pressure, renin activity, sympathetic nervous activity and renal sodium retention. Human hepatocytes treated with dexamethasone and the PPAR-[alpha] agonist Wy14,643 induced PPARA and gluconeogenic gene expression. These results identify hepatic activation of PPAR-[alpha] as a mechanism underlying glucocorticoid-induced insulin resistance., Author(s): Carlos Bernal-Mizrachi [1, 2]; Sherry Weng [1, 2]; Chu Feng [1, 2]; Brian N Finck [1, 5]; Russell H Knutsen [3]; Teresa C Leone [1, 5]; Trey Coleman [1, [...]

Hyperlipidemia promotes the chronic inflammatory disease atherosclerosis through poorly understood mechanisms. Atherogenic lipoproteins activate platelets, but it is unknown whether platelets contribute to early inflammatory atherosclerotic lesions. To address the role of platelet aggregation in diet-induced vascular disease, we studied [beta]3 integrin-deficient mice (lacking platelet integrin [alpha]11b/[beta]3 and the widely expressed nonplatelet integrin [alpha]v/[beta]3) in two models of atherosclerosis, apolipoprotein E (apoE)-null and low-density lipoprotein receptor (LDLR)-null mice. Unexpectedly, a high-fat, Western-type (but not a low-fat) diet caused death in two-thirds of the [[beta]3.sup.-/-]apo[E.sup.-/-] and half of the [[beta]3.sup.-/-]LDL[R.sup.-/-] mice due to noninfectious pneumonitis. In animals from both models surviving high-fat feeding, pneumonitis was absent, but aortic atherosclerosis was 2- to 6-fold greater in [[beta]3.sup.-/-] compared with [[beta].sup.+/+] littermates. Expression of CD36, CD40L, and CD40 was increased in lungs of [[beta]3.sup.-/-]LDL[R.sup.-/-] mice. Each was also increased in smooth muscle cells cultured from [beta]3-deficient mice and suppressed by retroviral reconstitution of [beta]3. These data show that the platelet defect caused by [alpha]11b[beta]3 deficiency does not impair atherosclerotic lesion initiation. They also suggest that [alpha]v[beta]3 has a suppressive effect on inflammation, the loss of which induces atherogenic mediators that are amplified by diet-induced hyperlipidemia.

Bergeron, Raynald, Jian Ming Ren, Kevin S. Cadman, Irene K. Moore, Pascale Perret, Marc Pypaert, Lawrence H. Young, Clay F. Semenkovich, and Gerald I. Shulman. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab 281: E1340-E1346, 2001.--The underlying mechanism by which skeletal muscle adapts to exercise training or chronic energy deprivation is largely unknown. To examine this question, rats were fed for 9 wk either with or without [beta]-guanadinopropionic acid ([beta]-GPA; 1% enriched diet), a creatine analog that is known to induce muscle adaptations similar to those induced by exercise training. Muscle phosphocreatine, ATP, and ATP/AMP ratios were all markedly decreased and led to the activation of AMP-activated protein kinase (AMPK) in the [beta]-GPA-fed rats compared with control rats. Under these conditions, nuclear respiratory factor-1 (NRF-1) binding activity, measured using a cDNA probe containing a sequence encoding for the promoter of [delta]-aminolevulinate (ALA) synthase, was increased by about eightfold in the muscle of [beta]-GPA-fed rats compared with the control group. Concomitantly, muscle ALA synthase mRNA and cytochrome c content were also increased. Mitochondrial density in both extensor digitorum longus and epitrochlearis from [beta]-GPA-fed rats was also increased by more than twofold compared with the control group. In conclusion, chronic phosphocreatine depletion during [beta]-GPA supplementation led to the activation of muscle AMPK that was associated with increased NRF-1 binding activity, increased cytochrome c content, and increased muscle mitochondrial density. Our data suggest that AMPK may play an important role in muscle adaptations to chronic energy stress and that it promotes mitochondrial biogenesis and expression of respiratory proteins through activation of NRF-1. nuclear respiratory factor-1; muscle adaptation; [delta]-aminolevulinate synthase; cytochrome c; [beta]-guanadinopropionic acid Received 9 July 2001; accepted in final form 21 August 2001

The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was targeted in mice. PGC-1alpha null (PGC-1alpha-/-) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha-/- mice. With age, the PGC-1alpha-/- mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha-/- mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha-/- mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha-/- mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha-/- mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha-/- mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha-/- mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

To determine whether uncoupling respiration from oxidative phosphorylation in skeletal muscle is a suitable treatment for obesity and type 2 diabetes, we generated transgenic mice expressing the mitochondrial uncoupling protein (Ucp) in skeletal muscle. Skeletal muscle oxygen consumption was 98% higher in Ucp-L mice (with low expression) and 246% higher in Ucp-H mice (with high expression) than in wild-type mice. Ucp mice fed a chow diet had the same food intake as wild-type mice, but weighed less and had lower levels of glucose and triglycerides and better glucose tolerance than did control mice. Ucp-L mice were resistant to obesity induced by two different high-fat diets. Ucp-L mice fed a high-fat diet had less adiposity, lower levels of glucose, insulin and cholesterol, and an increased metabolic rate at rest and with exercise. They were also more responsive to insulin, and had enhanced glucose transport in skeletal muscle in the setting of increased muscle triglyceride content. These data suggest that manipulating respiratory uncoupling in muscle is a viable treatment for obesity and its metabolic sequelae., Author(s): Bing Li [1, 2]; Lorraine A. Nolte [1, 2]; Jeong-Sun Ju [1]; Dong Ho Han [1]; Trey Coleman [1]; John O. Holloszy [1]; Clay F. Semenkovich (corresponding author) [1] [...]

Gel mobility shift assays were undertaken to demonstrate the presence of a cytoplasmic factor that binds to the amino terminus of the fatty acid synthase (FAS) mRNA in human Hep G2 cells. Electrophoretic analysis reveals a 178-kiloDalton phosphoprotein induced by glucose. This protein binds specifically to a novel repetitive element in the amino terminal of FAS mRNA and is believed to modulate posttranscriptional control of this mRNA.