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Infusion of TNF-α results in increased insulin resistance in rat and human skeletal muscle cells incubated in culture (21), although TNF-α neutralization over a period of 4 weeks had no effect on insulin sensitivity in obese type 2 diabetic subjects (22). The role of excess lipid turnover and cytokine production from adipose tissue, especially in obese patients, could potentially be very important in the overall insulin resistance and excess substrate supply that drives maternal-fetal energy transfer and increased neonatal adiposity.

The cellular mechanisms underlying a greater risk of cardiometabolic disease in adult offspring exposed to maternal obesity are not known. Our prior work found reduced skeletal muscle mitochondrial metabolism and insulin sensitivity in offspring exposed to maternal (m) Western-style diet (WD), even when weaned onto a control diet (CD) in Japanese macaques. Here, we performed multiple comparisons of differentially expressed (DE) genes in skeletal muscle from lean juvenile offspring to test hypotheses specific to (1) the lasting effects of maternal diet composition and/or maternal adiposity on gene expression and (2) the transcriptional response to a chronic postweaning (pw)WD with and without prior exposure to mWD. Overall, we identified maternal (m)WD, and not maternal adiposity, as a principal driver of DE in offspring muscle even years after exposure with few differences observed in patterns of DE between offspring of lean vs. obese mWD dams. Transcriptional response to the pwWD was robust in mCD offspring but blunted by mWD, particularly in males, suggesting a potential priming of gene expression. KEGG enrichment analysis and assessment of top DE genes identified changes in key pathways associated with dysregulated metabolism and RNA processing. We conclude that mWD has a significant and lasting impact on offspring gene expression which likely contributes to observed skeletal muscle insulin resistance and metabolic dysregulation in these offspring.

The prevalence of maternal obesity is increasing in the United States. Offspring born to women with obesity or poor glycemic control have greater odds of becoming obese and developing metabolic disease later in life. Our group has utilized a macaque model to study the metabolic effects of consumption of a calorically-dense, Western-style diet (WSD; 36.3% fat) during pregnancy. Here, our objective was to characterize the effects of WSD and obesity, alone and together, on maternal glucose tolerance and insulin levels in dams during each pregnancy. Recognizing the collinearity of maternal measures, we adjusted for confounding factors including maternal age and parity. Based on intravenous glucose tolerance tests, dams consuming a WSD showed lower glucose area under the curve during first study pregnancies despite increased body fat percentage and increased insulin area under the curve. However, with (1) prolonged WSD feeding, (2) multiple diet switches, and/or (3) increasing age and parity, WSD was associated with increasingly higher insulin levels during glucose tolerance testing, indicative of insulin resistance. Our results suggest that prolonged or recurrent calorically-dense WSD and/or increased parity, rather than obesity per se, drive excess insulin resistance and metabolic dysfunction. These observations in a highly relevant species are likely of clinical and public health importance given the comparative ease of maternal dietary modifications relative to the low likelihood of successfully reversing obesity in the course of any given pregnancy.

Background Reversible ε‐amino acetylation of lysine residues regulates transcription as well as metabolic flux; however, roles for specific lysine acetyltransferases in skeletal muscle physiology and function are unknown. In this study, we investigated the role of the related acetyltransferases p300 and cAMP response element‐binding protein‐binding protein (CBP) in skeletal muscle transcriptional homeostasis and physiology in adult mice. Methods Mice with skeletal muscle‐specific and inducible knockout of p300 and CBP (PCKO) were generated by crossing mice with a tamoxifen‐inducible Cre recombinase expressed under the human α‐skeletal actin promoter with mice having LoxP sites flanking exon 9 of the Ep300 and Crebbp genes. Knockout of PCKO was induced at 13–15 weeks of age via oral gavage of tamoxifen for 5 days to both PCKO and littermate control [wildtype (WT)] mice. Body composition, food intake, and muscle function were assessed on day 0 (D0) through 5 (D5). Microarray and tandem mass tag mass spectrometry analyses were performed to assess global RNA and protein levels in skeletal muscle of PCKO and WT mice. Results At D5 after initiating tamoxifen treatment, there was a reduction in body weight (−15%), food intake (−78%), stride length (−46%), and grip strength (−45%) in PCKO compared with WT mice. Additionally, ex vivo contractile function [tetanic tension (kPa)] was severely impaired in PCKO vs. WT mice at D3 (~70–80% lower) and D5 (~80–95% lower) and resulted in lethality within 1 week—a phenotype that is reversed by the presence of a single allele of either p300 or CBP. The impaired muscle function in PCKO mice was paralleled by substantial transcriptional alterations (3310 genes; false discovery rate < 0.1), especially in gene networks central to muscle contraction and structural integrity. This transcriptional uncoupling was accompanied by changes in protein expression patterns indicative of impaired muscle function, albeit to a smaller magnitude (446 proteins; fold‐change > 1.25; false discovery rate < 0.1). Conclusions These data reveal that p300 and CBP are required for the control and maintenance of contractile function and transcriptional homeostasis in skeletal muscle and, ultimately, organism survival. By extension, modulating p300/CBP function may hold promise for the treatment of disorders characterized by impaired contractile function in humans.

Maternal obesity affects nearly one-third of pregnancies and is a major risk factor for nonalcoholic fatty liver disease (NAFLD) in adolescent offspring, yet the mechanisms behind NAFLD remain poorly understood. Here, we demonstrate that nonhuman primate fetuses exposed to maternal Western-style diet (WSD) displayed increased fibrillar collagen deposition in the liver periportal region, with increased ACTA2 and TIMP1 staining, indicating localized hepatic stellate cell (HSC) and myofibroblast activation. This collagen deposition pattern persisted in 1-year-old offspring, despite weaning to a control diet (CD). Maternal WSD exposure increased the frequency of DCs and reduced memory CD4+ T cells in fetal liver without affecting systemic or hepatic inflammatory cytokines. Switching obese dams from WSD to CD before conception or supplementation of the WSD with resveratrol decreased fetal hepatic collagen deposition and reduced markers of portal triad fibrosis, oxidative stress, and fetal hypoxemia. These results demonstrate that HSCs and myofibroblasts are sensitive to maternal WSD-associated oxidative stress in the fetal liver, which is accompanied by increased periportal collagen deposition, indicative of early fibrogenesis beginning in utero. Alleviating maternal WSD-driven oxidative stress in the fetal liver holds promise for halting steatosis and fibrosis and preventing developmental programming of NAFLD.

Akt2 Is Essential for the Full Effect of Calorie Restriction on Insulin-Stimulated Glucose Uptake in Skeletal Muscle Carrie E. McCurdy 1 and Gregory D. Cartee 2 1 Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 2 Division of Kinesiology, University of Michigan, Ann Arbor, Michigan Address correspondence and reprint requests to Gregory D. Cartee, PhD, University of Michigan, Division of Kinesiology, Room 3040E, 401 Washtenaw Ave., Ann Arbor, MI 48109-2214. E-mail: gcartee{at}umich.edu Abstract Brief calorie restriction (CR; 20 days of 60% of ad libitum [AL] intake) improves insulin-stimulated glucose transport, concomitant with enhanced phosphorylation of Akt2. The purpose of this study was to determine whether Akt2 is essential for the calorie restriction–induced enhancement in skeletal muscle insulin sensitivity. We measured insulin-stimulated 2-deoxyglucose (2DG) uptake in isolated extensor digitorum longus (EDL) and soleus muscles from male and female wild-type (WT) and Akt2-null (knockout [KO]) mice after ad libitum or calorie-restricted (20 days at 60% of AL) feeding. In WT mice, calorie restriction significantly enhanced insulin-stimulated 2DG uptake in both muscles regardless of sex. However, in KO mice, calorie restriction did not enhance insulin-stimulated 2DG in male or female EDL or in female soleus. Only in male KO soleus did calorie restriction significantly increase insulin-stimulated 2DG through an Akt2-independent mechanism, although 2DG uptake of the KO-CR group was reduced compared with the WT-CR soleus group. Akt2 serine phosphorylation was enhanced approximately two- to threefold in insulin-stimulated WT-CR versus WT-AL muscles. Calorie restriction induced an ∼1.5- to 2-fold elevation in Akt1 phosphorylation of insulin-treated muscles, regardless of genotype, but this increase was insufficient to replace Akt2 for insulin-stimulated 2DG in Akt2-deficient muscles. These results indicate that Akt2 is essential for the full effect of brief calorie restriction on insulin-stimulated glucose uptake in skeletal muscle with physiologic insulin. 2DG, 2-deoxyglucose AMPK, AMP-activated protein kinase EDL, extensor digitorum longus IRS, insulin receptor substrate KHB, Krebs-Henseleit buffer PI3K, phosphatidylinositol 3-kinase TBST, Tris-buffered saline with 0.1% Tween Footnotes Accepted February 15, 2005. Received October 26, 2004. DIABETES

Skeletal Muscle–Specific Deletion of Lipoprotein Lipase Enhances Insulin Signaling in Skeletal Muscle but Causes Insulin Resistance in Liver and Other Tissues Hong Wang 1 , Leslie A. Knaub 1 , Dalan R. Jensen 1 , Dae Young Jung 2 , Eun-Gyoung Hong 2 , Hwi-Jin Ko 2 , Alison M. Coates 1 , Ira J. Goldberg 3 , Becky A. de la Houssaye 4 , Rachel C. Janssen 4 , Carrie E. McCurdy 4 , Shaikh M. Rahman 4 , Cheol Soo Choi 5 , Gerald I. Shulman 6 , Jason K. Kim 2 , Jacob E. Friedman 4 and Robert H. Eckel 1 1 Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado 2 Department of Cellular & Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 3 Department of Medicine, Columbia University, New York City, New York 4 Department of Pediatrics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado 5 Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 6 Department of Internal Medicine, Department of Cellular & Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut Corresponding author: Robert H. Eckel, robert.eckel{at}uchsc.edu Abstract OBJECTIVE— Skeletal muscle–specific LPL knockout mouse (SMLPL −/− ) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight, and composition. RESEARCH DESIGN AND METHODS— Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulin-signaling molecules were compared in skeletal muscle and liver of SMLPL −/− and control mice. RESULTS— Nine-week-old SMLPL −/− mice showed no differences in body weight, fat mass, or whole-body insulin sensitivity, but older SMLPL −/− mice had greater weight gain and whole-body insulin resistance. High-fat diet feeding accelerated the development of obesity. In young SMLPL −/− mice, insulin-stimulated glucose uptake was increased 58% in the skeletal muscle, but was reduced in white adipose tissue (WAT) and heart. Insulin action was also diminished in liver: 40% suppression of hepatic glucose production in SMLPL −/− vs. 90% in control mice. Skeletal muscle triglyceride was 38% lower, and insulin-stimulated phosphorylated Akt (Ser473) was twofold greater in SMLPL −/− mice without changes in IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase activity. Hepatic triglyceride and liver X receptor, carbohydrate response element–binding protein, and PEPCK mRNAs were unaffected in SMLPL −/− mice, but peroxisome proliferator–activated receptor (PPAR)-γ coactivator-1α and interleukin-1β mRNAs were higher, and stearoyl–coenzyme A desaturase-1 and PPARγ mRNAs were reduced. CONCLUSIONS— LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition. Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 24 October 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. See accompanying commentary, p. 16 . Accepted October 8, 2008. Received December 29, 2007. DIABETES

Background Previous studies of lipoproteins in patients with sepsis have been performed on density fractions isolated by conventional ultracentrifugation that are heterogeneous and provide no information about the cargo of apoproteins present in the immunochemically distinct subclasses that populate the density classes. Since apoproteins are now known to have important roles in host defense, we have separated these subclasses according to their apoprotein content and characterized their changes during experimental endotoxemia in human volunteers. Methods We have studied apoB- and apoA containing lipoprotein subclasses in twelve healthy male volunteers before and for 8 h after a single dose of endotoxin (ET; 2 μg/kg) to stimulate inflammation. Results After endotoxin, TG, TC, apoB and the apoB-containing lipoprotein cholesterol-rich subclass LpB and two of the three triglyceride-rich subclasses (TGRLP: Lp:B:C, LpB:C:E+ LpB:E) all declined. In contrast, the third TGRLP, LpA-II:B:C:D:E (“complex particle”), after reaching a nadir at 4 h rose 49% above baseline, p  = .006 at 8 h and became the dominant particle in the TGRLP pool. This increment exceeds the threshold of > 25% change required for designation as an acute phase protein. Simultaneous decreases in LpA-I:A-II and LpB:C:E + LpB:E suggest that these subclasses undergo post-translational modification and contribute to the formation of new LpA-II:B:C:D:E particles. Conclusions We have identified a new acute phase lipoprotein whose apoprotein constituents have metabolic and immunoregulatory properties applicable to host defense that make it well constituted to engage in the APR.

Maternal obesity is thought to increase the offspring's risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD.