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«THE EFFECT OF OVERFEEDING AND OBESITY ON CANINE ADIPOSE TISSUE AND SKELETAL MUSCLE TRANSCRIPTOMES BY RYAN WALTER GRANT DISSERTATION Submitted in ...»

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THE EFFECT OF OVERFEEDING AND OBESITY ON CANINE ADIPOSE TISSUE AND

SKELETAL MUSCLE TRANSCRIPTOMES

BY

RYAN WALTER GRANT

DISSERTATION

Submitted in partial fulfillment of the requirements

for the degree of Doctor of Philosophy in Nutritional Sciences

in the Graduate College of the University of Illinois at Urbana-Champaign, 2011 Urbana, Illinois

Doctoral Committee:

Professor Sharon M. Donovan, Chair Associate Professor Kelly S. Swanson, Director of Research Associate Professor Thomas K. Graves Associate Professor Manabu T. Nakamura   Abstract Overweight dogs have a reduced life expectancy and increased risk of chronic disease.

During obesity development, adipose tissue undergoes major expansion and remodeling, but the biological processes involved are not well understood. The objective of study 1 was to analyze global gene expression profiles of adipose tissue in dogs, fed a high-fat (47% kcal/g) diet, during the transition from a lean to obese phenotype. Nine female beagles were randomized to ad libitum (n=5) feeding or body weight maintenance (n=4). Subcutaneous adipose tissue biopsy, skeletal muscle biopsy and blood samples were collected, and dual x-ray absorptiometry measurements were taken at 0, 4, 8, 12, and 24 wk of feeding. Ad libitum feeding increased (P0.05) body weight, body fat mass, adipocyte size and serum leptin concentrations.

Microarrays displayed 1,665 differentially expressed genes in adipose tissue over time in the ad libitum fed dogs. Alterations were observed in many homeostatic processes including metabolism, oxidative stress, mitochondrial homeostasis, and extracellular matrix. Our data implies that during obesity development subcutaneous adipose tissue has a large capacity for expansion, which is accompanied by tissue remodeling and short-term adaptations to the metabolic stresses associated with ad libitum feeding. Gene expression changes between 12 and 24 wk indicate the end of an initial adaptive response to ad libitum feeding and the onset of a chronic obese state.

The objective of study 2 was to identify differentially expressed genes and enriched functional pathways between subcutaneous and gonadal adipose of lean and obese dogs at 24 wk of the animal experiment described in study 1. Subcutaneous adipocytes of obese dogs were larger than obese gonadal and lean subcutaneous and gonadal adipocytes. A total of 946 and 703 transcripts were differentially expressed between gonadal and subcutaneous adipose tissue in

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obese and lean dogs, respectively. Both lean and obese dog gene lists had enrichment of the complement and coagulation cascade, lysosomal and systemic lupus erythematosus pathways.

Obese dogs had enrichment of extracellular matrix-receptor interaction and renin-angiotensin system pathways. Lean dogs had enrichment of glutathione metabolism, focal adhesion, synthesis and degradation of ketone bodies and amino sugar metabolism. This study demonstrates that there are a core set of genes that differentiate adipose tissue depots regardless of obesity status, that may underlie differences in depot metabolism and inflammation.

Skeletal muscle, as a large and insulin-sensitive tissue, is an important contributor to metabolic homeostasis and energy expenditure. Only a limited number of studies have compared skeletal muscle gene expression of lean and obese dogs. The objective of study 3 was to identify genes and functional classes differentially expressed between lean and obese dog skeletal muscle at 24 wk of the animal experiment described in study 1. Microarrays displayed 77 differentially expressed skeletal muscle transcripts between lean and obese dogs. Alterations were observed in genes pertaining to the functional classes of signaling, transport, protein catabolism and proteolysis, protein modification, development, transcription and apoptosis, cell cycle and differentiation. The small amount of differentially expressed genes in skeletal muscle indicates that adipose tissue expansion may buffer skeletal muscle from the metabolic stresses associated with ad libitum feeding.

In study 1, zinc-alpha2 glycoprotein (ZAG) was highly expressed (up to 60-fold vs.

baseline) in subcutaneous adipose tissue during weight gain, with increased expression at 4, 8, and 12 wk. At 24 wk, however, ZAG expression had returned to basal levels. Studies in both humans and rodents suggest that adipose tissue ZAG expression is down-regulated during obesity. Therefore, the objective of study 4 was to determine if ZAG was increased with

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increasing body weight and body condition score in a clinical population of dogs. The clinical population studied had a narrow body condition score range (2-6), but wide body weight range (3.0-29.5 kg). ZAG expression (ZAG/cycophilin A) ranged from 0.68-3.13, but there was no influence (P0.05) of body condition score or body weight on its expression. Gonadal adipose tissue expression of ZAG was not influenced by body condition score in this clinical population, which could be due to the depot measured or lack of obese dogs in this population.

Our results indicate that adipose tissue has a large capacity to store and adapt to  excess calories during the transition from a lean to obese phenotype.  The capacity for  adipose tissue to expand may buffer skeletal muscle from the effects of excess calories  during this period.  Even though large phenotypic differences were noted between lean and  obese dogs, transcriptome analysis revealed a core set of genes differentiating  subcutaneous and gonadal adipose tissue in both groups. 

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Thanks to my wife for her love and support.

Thanks to Dr. Swanson for his mentoring and pushing me to succeed.

Thanks to my committee for their feedback and guidance.

Thanks to my labmates for listening to me rant about genes and pathways.

Thanks to my family for their support and understanding.

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List of Abbreviations

CHAPTER 1: Introduction

CHAPTER 2: Literature review

CHAPTER 3: Adipose tissue transcriptome changes during obesity development in female dogs

CHAPTER 4: Subcutaneous and gonadal adipose tissue transcriptome differences in lean and obese female dogs

CHAPTER 5: Skeletal muscle tissue transcriptome differences in lean and obese Female dogs

CHAPTER 6: Gonadal adipose tissue ZAG protein expression in a clinical population of dogs

CHAPTER 7: Summary

APPENDIX A: Differentially expressed genes in ad libitum fed dogs during diet-induced obesity

APPENDIX B: Enriched KEGG pathway gene transcripts differentially expressed between gonadal and subcutaneous adipose tissue in lean and obese dogs

CURRICULUM VITAE

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4-HNE 4-hydroxynonenal ACACA acetyl-CoA carboxylase-A ACVR2B activin receptor IIB ADRA2c adrenergic, alpha-2C-, receptor ADRB2 adrenergic, beta-2-, receptor BCAT2 branched chain amino acid aminotransferase 2 BCKDK branched chain ketoacid dehydrogenase kinase BCS body condition score BMP bone morphogenetic protein C1QA complement component 1, q subcomponent, A chain C1S complement component 1, s subcomponent C3 complement 3 C4 complement 4 C6 complement 6 C8 complement 8 CFB complement factor B CFI complement factor I CCL5 chemokine (C-C motif) ligand 5 CCRL2 chemokine receptor-like 2 CISH cytokine inducible SH2-containing protein COL1A1 collagen, type 1, alpha 1 COL3A1 collagen, type 3, alpha 1 COL4A1 collagen, type 4, alpha 1 COL6A1 collagen, type 6, alpha 1 CPT1B carnitine palitoyltransferase 1B CRP c-reactive protein DAVID Database for Annotation, Visualization and Integrated Discovery ECM extracellular matrix EIF4EBP eukaryotic translation initiation factor 4E binding protein ELOVL6 elongation of long chain fatty acids family member 6 ER endoplasmic reticulum ERK extracellular signal-regulated kinase FC fold change FDR false discovery rate GCRMA GeneChip Robust Multiarray Averaging GLUT4 glucose transporter 4 GPX glutathione peroxidase GS1 glycogen synthase 1 GST glutathione-s-transferase ID3 inhibitor of DNA binding 3 IL-6 interleukin-6 IRS-1 insulin receptor substrate-1 IRS-2 insulin receptor substrate-2 JNK c-jun N-terminal kinase

 viii  

KEGG Kyoto Encyclopedia of Genes and Genomes KRT18 keratin 18 LOX lysyl oxidase LPL lipoprotein lipase LPS lipopolysaccharide LTBP3 latent transforming growth factor beta binding protein 3 LY86 lymphocyte antigen 86 LY96 lymphocyte antigen 96 MCP-1 monocyte chemoattractant protein-1 MMP2 matrix metallopeptidase 2 MMP27 matrix metallopeptidase 27 MMP9 matrix metallopeptidase 9 NCBI National Center for Biotechnology Information NEFA non-esterified fatty acid NOC3L nucleolar complex associated 3 homolog NQO1 NAD(P)H dehydrogenase, quinone 1 OPA1 optic atrophy 1 PDK4 pyruvated dehydrogenase kinase, isozyme 4 PEA15 phosphoprotein enriched in astrocytes 15 PFKFB1 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 PGC1 PPAR-coactivator receptor 1 PPARγ peroxisome proliferator activated receptor-γ PVDF polyvinylidene fluoride qRT-PCR quantitative real-time polymerase chain reaction RUNX1T1 runt-related transcription factor 1 SEM standard error of the means SLC22A5 solute carrier family 22, member 5 SMAD5 SMAD family member 5 SOCS2 suppressor of cytokine signaling 2 STAT2 signal transducer and activator of transcription 2 TBS TRIS buffered saline TCF7L2 transcription factor 7-like 2 TG triglyceride THBS4 thrombospondin 4 TMEFF2 transmembrane protein with EGF-like and two follistatin-like domains 2 TLR toll like receptor TNFα tumor necrosis factor-α TREM2 triggering receptor expressed on myeloid cells 2 UCP2 uncoupling protein 2 UCP3 uncoupling protein 3 WIF1 WNT inhibitory factor XOR xanthine oxidoreductase ZAG zinc-alpha2 glycoprotein

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Dog obesity rates vary from 20-40% in Westernized societies [1]. Obesity in dogs reduces lifespan and increases risk for numerous chronic diseases [2, 3]. Common causes of obesity include overfeeding and lack of exercise [4]. Although obesity seems to be a simple imbalance between energy intake and expenditure, it induces changes in multiple tissues and organ systems, which contribute to metabolic dysfunction and disease risk. High-fat feeding and overfeeding total calories increase body fat and lead to insulin resistance and hyperlipidemia in the dog [5, 6]. Both liver and skeletal muscle becomes insulin-resistant during canine obesity.

Non-esterified fatty acids (NEFA) cause hepatic and muscular insulin resistance [7, 8]. Visceral adipose tissue has increase lipid metabolic activity and may be the source of NEFA and inflammatory mediators causing liver and skeletal insulin-resistance. Skeletal muscle plays an important role in insulin-stimulated glucose disposal and insulin resistance in skeletal muscle shifts glucose to other metabolically active tissues such as the liver and adipose tissue.

Adipose tissue releases NEFA, and increased NEFA release as a result of adipose tissue dysfunction could play a causative role in metabolic perturbations associated with obesity.

Mechanisms of adipose tissue dysfunction are relatively unexplored in the dog, compared to humans and rodents. During diet-induced obesity in C57BL/6 mice, adipose tissue is infiltrated by macrophages, which dispose of lipid droplets from dead adipocytes [9]. The uptake of lipid droplets is important for adipose tissue remodeling, which is associated with changes in insulin sensitivity [10]. However, macrophages infiltrating adipose tissue also secrete cytokines that contribute to systemic low-grade inflammation associated with obesity. Canine adipocytes express inflammatory cytokines, which are increased by treatment with tumor necrosis factor-α

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or lipopolysacchride [11]. Inflammatory cytokines, along with NEFA, are known to reduce insulin sensitivity in multiple tissues and play a causative role in metabolic perturbations associated with obesity.

Whole genome microarrays have been utilized to determine adipose tissue and skeletal muscle functional differences between lean and obese rodents and humans. These studies have been informative, but many unanswered questions remain. Most studies have focused on differences between lean and obese individuals, without regard to the biological processes and changes that occur over the course of obesity development.

The overall objective of this dissertation was to use microarray technology to identify differentially expressed genes and functional pathways during early weight gain in the dog, and to relate these changes in gene expression to circulating hormones and metabolites. The objective of study 1 was to identify genes and functional gene classes differentially expressed over 24 wk of ad libitum feeding in the dog. We hypothesized that over this time course, adipose tissue would have increased expression of transcripts associated with macrophages and inflammation, extracellular matrix production, and oxidative stress response. The objective of study 2 was to identify genes and functional gene classes differentially expressed between subcutaneous and gonadal adipose tissue in lean and obese dogs. We hypothesized that gonadal adipose tissue would have increased expression of carbohydrate and lipid metabolism genes and inflammatory markers, and these differences would be larger in obese as compared to lean animals. The objective of study 3 was to identify genes and functional gene classes differentially expressed in skeletal muscle between lean and obese dogs. We hypothesized that obese dogs would have gene expression patterns indicative of metabolic dysfunction. Subcutaneous adipose tissue zinc-alpha2 glycoprotein (ZAG) mRNA was highly increased during weight gain. The

–  –  –

objective of study 4 was to determine how ZAG expression is affected by body weight and body condition score in a clinical population. We hypothesized that dogs with a higher body condition score would have increased expression of ZAG, but extremely obese dogs would have reduced ZAG expression.

References



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