Factors affecting adipose tissue development in chickens: A review

Factors affecting adipose tissue development in chickens: A review Guoqing Wang,∗ Woo Kyun Kim,† Mark A. Cline,∗ and Elizabeth R. Gilbert∗,1 ∗

Department of Animal and Poultry Sciences, Virginia Tech, Blacksburg, Virginia 24061; and † Department of Poultry Science, University of Georgia, Athens, GA 30602 tissue development and lipid metabolism. Transcription factors, such as peroxisome proliferator-activated receptor γ , CCAAT/enhancer-binding proteins α and β , and sterol regulatory element binding proteins orchestrate a series of cellular events that lead to an increase in activity of fatty acid transport proteins and enzymes that are responsible for triacylglycerol synthesis. Understanding the mechanisms underlying adipose tissue development may provide a practical strategy to affect body composition of the commercial broiler while providing insights on diets that maximize conversion into muscle rather than fat and affect depot-dependent deposition of lipids. Because of the propensity to overeat and become obese, the broiler chicken also represents an attractive biomedical model for eating disorders and obesity in humans.

ABSTRACT The intense genetic selection for rapid growth in broilers has resulted in an increase in voluntary feed intake and growth rate, accompanied by increased fat deposition in adipose tissue depots throughout the body. Adipose tissue expansion is a result of the formation of adipocytes (several processes collectively referred to as adipogenesis) and cellular accumulation of triacylglycerols inside lipid droplets. In mammals, different anatomical depots are metabolically distinct. The molecular and cellular mechanisms underlying adipose tissue development have been characterized in mammalian models, whereas information in avian species is scarce. The purpose of this review is to describe factors regulating adipogenesis in chickens, with an emphasis on dietary factors and the broiler. Results from many studies have demonstrated effects of dietary nutrient composition on adipose

Key words: adipogenesis, adipose, chicken, diet, macronutrient 2017 Poultry Science 0:1–13 http://dx.doi.org/10.3382/ps/pex184

INTRODUCTION

paucity of knowledge on adipose tissue development in avian species. This review focuses on summarizing major factors that affect adipose tissue development in chickens, with an emphasis on dietary macronutrients.

With intensive selection for meat production, the growth rates of broiler chickens have increased by over 300% (Knowles et al., 2008), which has been accompanied by increased body fat deposition, more skeletal disorders, and greater incidence of metabolic diseases and mortality (Leeson and Zubair, 1997; Hafez and Hauck, 2005). Increased fat accumulation in broiler chickens raises economic concerns (Yu and Robinson, 1992; Urdaneta-Rincon and Leeson, 2002), because excessive fat can hinder processing and may also result in rejection of the meat product by consumers, as well as reducing feed efficiency and carcass yield (Sahraei, 2012). In mammals, the molecular and cellular mechanisms underlying adipose tissue development have been well studied. The development of adipose tissue is a consequence of both multiplication of new adipocytes (hyperplasia) and increased accumulation of lipid in adipocytes (hypertrophy). However, there is still a

ADIPOGENESIS AND ADIPOSE TISSUE EXPANSION Adipogenesis Overview Mesenchymal stem cells are multipotent stromal cells with the capacity to differentiate into a variety of cell types, such as myoblasts, osteoblasts, chondrocytes, and adipocytes (Zuk et al., 2002). Thus, adipocytes are derived from connective tissues, and once a mesenchymal stem cell is committed to the preadipocyte pathway, maturation and growth is completed by synchronized actions of various transcription factors, discussed in later sections of this review. Preadipocytes can continue to proliferate, but once committed to becoming an adipocyte, terminal differentiation is characterized by the accumulation of lipids (i.e., triacylglycerol (TAG)). Tissue development is associated with collagen synthesis and angiogenesis to provide structural support, nutrients, and oxygen to the cells. Multiple lipid droplets

 C 2017 Poultry Science Association Inc. Received September 23, 2016. Accepted June 13, 2017. 1 Corresponding author: [email protected]

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Figure 1. The liver and adipose tissue are the 2 main sites of de novo fatty acid synthesis in higher vertebrates. In avian species, the liver is the main site of de novo lipogenesis, where glucose is catabolized to acetyl coA, which is then converted into fatty acids and cholesterol. In the liver, cholesterol and triacylglycerols (TAGs) are incorporated into very low density lipoproteins (VLDLs) to be transported to other tissues via the circulation. Lipoprotein lipase (LPL), anchored to endothelial cells lining tissues throughout the body, facilitates fatty acid delivery to peripheral tissues by hydrolyzing ester bonds of TAG. As more TAGs are removed, VLDL change in composition and become intermediate density lipoproteins (IDLs), which are then converted to low density lipoproteins (LDLs) as more fatty acids are sequestered. In the lipid droplet of the adipocyte, lipolysis of stored TAG is catalyzed sequentially by adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL) and monoglyceride lipase (MGL). ATGL breaks down TAG to diacyglycerol (DAG) and one fatty acid. HSL and MGL catalyze fatty acid removal from DAG and monoacyglycerol, respectively. Parts of the figure are adapted (Ricoult and Manning, 2013).

(LDs) that form inside the differentiating cell (i.e., multilocular) start to coalesce into a single droplet (i.e., unilocular) during cellular maturation.

Hyperplasia and Hypertrophy The cellular development of adipose tissue thus includes both an increase in cell size (hypertrophy) and an increase in cell number (hyperplasia). Both adipocyte number and size increase with age, which show a positive correlation with body mass and fat pad weight in chickens (Cartwright, 1991). Thus, hyperplasia and hypertrophy of adipocytes contribute to fat accumulation in chickens, but with different magnitudes of contribution to the volume and weight of the distinct adipose tissue depots. During chicken embryonic adipose tissue development, preadipocyte hyperplasia dominates, followed by hypertrophy to establish immature adipocytes that are receptive to lipid deposition (Jo et al., 2009). In Leghorns and broilers, hyperplasia is induced in neck and leg fat pads between embryonic d 12 and d 14, followed by slowing rates of hyperplasia as embryos reach d 18 (Chen et al., 2014). Most of the adipocytes are unilocular once the embryo reaches d 14 of incubation, with multilocular cells almost undetectable at this stage, indicating that chicken adipocytes undergo rapid maturation during embryonic development (Chen et al., 2014).

Lipid Droplet Composition Lipid droplets, which represent the majority of the volume of an adipocyte, are fat-storing organelles composed of a hydrophobic core of TAG and cholesterol esters. LDs can be formed in nearly all cells. In the LD core, the primary neutral lipids are sterol esters

and TAG, with the primary form being TAG in LDs of adipocytes. The hydrophobic core is separated from the aqueous cytosol by a phospholipid monolayer that contains various proteins (Walther and Farese, 2012), including enzymes involved in lipid synthesis, lipases, and membrane-trafficking and structural proteins (Guo et al., 2009).

De Novo Fatty Acid Synthesis The synthesis of TAGs in adipocytes requires a steady supply of free fatty acids. The liver and adipose tissue are the two main sites of de novo fatty acid synthesis in higher vertebrates (Figure 1). In avian species, the liver is the main site of de novo lipogenesis, where glucose is catabolized to acetyl-CoA, which is then converted into fatty acids and cholesterol. In the liver, cholesterol and TAG are incorporated into very low density lipoproteins (VLDLs) to be transported to other tissues via the circulation.

TAG Synthesis in Adipose Tissue TAG synthesis requires both nonesterified fatty acids (NEFAs) and glycerol 3-phosphate. The majority of fatty acids in the adipose tissue are taken up as fatty acids from TAG in plasma lipoproteins (e.g., VLDL) that are synthesized and packaged by the liver. Fatty acids may also be acquired from dietary fat delivered to the circulation from the intestine as chylomicrons (Griffin and Hermier, 1988). Thus, the fatty acid composition of the diet in non-ruminant species has a direct bearing on the fatty acid profile of lipids stored in adipose tissue. In chickens, long-chain fatty acids are assembled into packages called “portomicrons” that enter directly into the portal blood from the small intestine, with the lipid composition and size of lipoproteins

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closely resembling that of rat chylomicrons (Noyan et al., 1964; Bensadoun and Rothfeld, 1972). The hydrolysis of TAG in VLDLs is catalyzed by lipoprotein lipase (LPL) on endothelial cells lining the adipose tissue, a rate-limiting step in fat accretion in chickens (Sato et al., 1999). Therefore, in chickens, fatty acids for TAG synthesis and adipose tissue expansion are acquired from plasma VLDLs and portomicrons. The glycerol generated from the hydrolysis of TAG cannot be re-utilized to esterify fatty acids due to the lack of glycerol kinase in the adipose tissue. During fasting, adipose tissue obtains the glycerol 3-phosphate required for TAG synthesis from pyruvate via gluconeogenesis or glucose via glycolysis (Vaughan, 1962; Ballard et al., 1967; Gorin et al., 1969; Reshef et al., 1970). The process of adipocyte hypertrophy involves the continued accumulation of TAG inside the LD and “stretching” of the cell. Acyl-CoA is synthesized from fatty acids and CoA. For glycerolipid biosynthesis, the acylation of glycerol 3-phosphate is the first and committed step. The reaction to produce 1-acyl-sn-glycerol 3phosphate (lysophosphatidate (LPA)) is catalyzed by acyl-CoA: glycerol-sn-3-phosphate acyltransferase (GPAT) (Kent, 1995). Phosphatidate is synthesized by the acylation of LPA in a reaction catalyzed by acyl-CoA:1-acylglycerol-sn-3-phosphate acyltransferase (AGPAT). The phosphatidate formation catalyzed by AGPAT marks a central branch point in lipid biosynthetic pathways (Kent, 1995). One of the possible routes for phosphatidate is dephosphorylation by phosphatidic acid phosphatase to produce diacylglycerol (DAG) (Jamal et al., 1991). As the final step in TAG synthesis, diglyceride acyltransferase (DGAT) catalyzes the formation of TAG from DAG and fatty acyl-CoA.

Lipolysis When animals are not in an energy-deficient state, NEFAs originate from ingested TAG, whereas plasma NEFAs come almost entirely from hydrolysis of TAG in the adipose tissue during the fasting state (Karpe et al., 2011). Net accretion of fat is the balance between intestinally absorbed fat from the diet, fatty acid and TAG synthesis, and fat breakdown. Lipolysis is the mobilization of NEFAs from stored TAG, which occurs sequentially through a series of hydrolysis reactions (Figure 1). Adipose triglyceride lipase (ATGL), also known as desnutrin, is a rate-limiting enzyme that catalyzes hydrolysis of the first ester bond of a TAG inside the LD to release a fatty acid and DAG (Villena et al., 2004; Zimmermann et al., 2004). The action of ATGL is followed by hormone-sensitive lipase (HSL) and monoacylglycerol lipase (MGL) (Morak et al., 2012). HSL hydrolyzes DAGs, and MGL liberates the final fatty acid from the glycerol backbone. In mammalian cells, activation of HSL is achieved by phosphorylation,

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which occurs via cyclic AMP-dependent protein kinase (Yeaman, 1990). Members of the PAT family of proteins, originally named for perilipin, adipose differentiation-related protein and tail interacting protein 47, serve important functions in regulating lipolysis (Sztalryd et al., 2006; Dalen et al., 2007). It appears that there is no HSL orthologue in the chicken genome (Sato et al., 2010). NEFAs are released into the circulation and transported to other tissues, such as skeletal and cardiac muscles and the liver, for β -oxidation to generate ATP. The major proteins that are involved in fatty acid transport in mammals are CD36/FAT (fatty acid translocase), fatty acid transport proteins (FATPs) and fatty acid binding proteins (FABPs), which have also been described in avian adipose tissues (Abumrad et al., 1999; Shu et al., 2009; Wang et al., 2012; Qi et al., 2013). Glycerol is transported to the liver, where it feeds into glycolysis to provide energy or can be used in gluconeogenesis.

Metabolic Differences Between Adipose Tissue Depots The physiology of different fat depots in mammals has been intensely studied, and has led to the consensus that different fat depots from various body regions are metabolically distinct. Subcutaneous fat has been reported to act as a buffer for the daily incorporation of dietary fat, preventing other tissues from receiving excessive lipids that can lead to lipotoxicity (Frayn, 2002). However, visceral fat (body fat stored within the abdominal cavity) is related to metabolic disorders (Pascot et al., 2000). In avian species, there is a paucity of knowledge regarding the metabolic characteristics of different fat depots. Our group reported that the average size of adipocytes was similar between abdominal and subcutaneous fat in chickens, while gene expression profiles of adipogenesis-associated factors differed (Zhang et al., 2014a). From an agricultural perspective, subcutaneous and abdominal fat can be regarded as waste in the slaughterhouse, while intramuscular fat may be regarded as favorable in relation to meat quality. The growth pattern of fat depots can be altered by dietary fatty acid composition. For instance, consumption of a diet containing more unsaturated than saturated fatty acids (SFAs) was associated with a 9 and 30% reduction in subcutaneous and abdominal fat, respectively, at 42 d posthatch in broilers (Ferrini et al., 2008).

Chickens as a Model to Study Adipose Development Chickens have been widely used for developmental and immunology studies because of several advantages as a model. Development occurs inside of the egg, is independent of maternal influence and manipulations,

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Figure 2. Transcription factors that orchestrate adipocyte development. Parts of the figure are adapted (Sarjeant and Stephens, 2012; Stephens, 2012). Abbreviations: EBF1, early B cell factor 1; Zfp423, zinc finger protein 423; KLFs, Kr¨ uppel-like transcription factors; C/EBPs, CCAAT/enhancer binding proteins; PPARγ , peroxisome proliferator-activated receptor γ ; SREBP-1, sterol regulatory element binding protein 1.

and viewing can be accomplished easily through introducing holes into the eggshell. Chickens are also a model for studies of adipose tissue biology and human metabolic disorders. Commercial broiler chickens have been intensely selected for growth rate, meat yield, and feed conversion efficiency over the past 70 years. This increase in growth has been accompanied by an increase in voluntary food intake, increased fat deposition in the body, and higher incidence of metabolic diseases (Zubair and Leeson, 1996; Hafez and Hauck, 2005). Similar to humans, but unlike pigs and rodents, chickens use the liver rather than adipose tissue as the main site of de novo lipid synthesis (Leveille et al., 1975; Shrago and Spennetta, 1976). Because of natural hyperglycemia (up to 200 mg/dL in fasting state) and a relative resistance to the effects of insulin in insulindependent tissues such as skeletal muscle and adipose, chickens mimic the early stages of type 2 diabetes in humans (Chen et al., 1945; Braun and Sweazea, 2008). Therefore, understanding the mechanisms of adipose tissue development in chickens can benefit the poultry industry and also provide insight into biomedical research.

TRANSCRIPTION FACTORS INVOLVED IN ADIPOGENESIS Various signaling pathways are involved in the commitment of mesenchymal stem cells towards an adipogenic lineage, including the β -catenin-dependent Wnt and Hedgehog signaling pathways (James, 2013). Wnt signaling family members suppress the early stages of adipogenesis, maintaining preadipocytes in an undifferentiated state via inhibition of peroxisome proliferator-activated receptor γ (PPARγ ) and CCAAT/enhancer binding protein-α (C/EBPα) (James, 2013). Similar to Wnt, Hedgehog signals also act to repress adipogenesis through induction of anti-adipogenic transcription factors such as GATA binding protein 2 (GATA2). The differentiation of preadipocytes and regulation of lipid synthesis and

metabolism are processes mediated by various transcription factors (Figure 2). Early transcriptional regulators C/EBPβ and C/EBPδ are expressed transiently, followed by the induction of key transcription factors PPARγ and C/EBPα that coordinate the transcriptional regulation of a variety of adipocyte-associated genes (Rosen and MacDougald, 2006). PPARγ is considered to be the “master” regulator of adipogenesis. Its expression is upregulated very early during differentiation (Tontonoz et al., 1994). Both in vitro and in vivo studies showed that the formation of the adipocyte cannot be completed without PPARγ (Barak et al., 1999; Rosen et al., 1999). Terminal differentiation is promoted by the activation of PPARγ , which is achieved through the induction of a variety of differentiation-dependent genes that are crucial for TAG uptake and storage, such as fatty acid-binding protein 4 (FABP4), LPL, and others. The importance of PPARγ in avians is also confirmed by a report that the suppression of PPARγ mRNA by small-interfering RNA inhibited differentiation and promoted proliferation of chicken preadipocytes (Wang et al., 2008). In mammals, C/EBPα is induced later than PPARγ , and is a critical regulator of adipocyte differentiation; expression of C/EBPα is positively regulated by PPARγ (Tamori et al., 2002). Although PPARγ is able to drive cells towards the adipogenic program in the absence of C/EBPα, C/EBPα is incapable of inducing adipogensis without PPARγ (Rosen et al., 2002). The zinc finger protein 423 (ZFP423) was identified as a regulator of preadipocyte cell determination and is more abundant in preadipose than nonpreadipose fibroblasts (Gupta et al., 2010). Inhibition of ZFP423 in a murine preadipocyte cell line (3T3L1) blocks PPARγ expression and adipogenic differentiation, whereas ectopic expression of ZFP423 in nonadipogenic fibroblasts (NIH 3T3) induces expression of PPARγ in undifferentiated cells and enhances adipogenesis once cells have been induced to differentiate (Gupta et al., 2010).

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Kr¨ uppel-like transcription factors (KLFs) and sterol regulatory element binding proteins (SREBPs) are other transcription factors that facilitate adipocyte maturation. KLF5 is activated by C/EBPβ and C/EBPδ , and acting jointly with these C/EBPs, contributes to the induction of PPARγ (Oishi et al., 2005). Other members of the KLF family, such as KLF6 and KLF15, promote adipogenesis (Li et al., 2005; Mori et al., 2005); however, there are also KLF members that are reported to be anti-adipogenic. For instance, KLF2 binding suppresses transcription from the PPARγ promoter (Banerjee et al., 2003; Kanazawa et al., 2005) and KLF7 enhances chicken preadipocyte proliferation and suppresses differentiation (Zhang et al., 2013). GATA2 is reported to be a preadipocyte-specific factor that promotes preadipocyte activity (Shang et al., 2014) as its overexpression inhibited chicken preadipocyte differentiation (Zhang et al., 2012). Preadipocyte factor-1 (Pref-1) is a transmembrane protein that is highly expressed in preadipocytes and also acts to inhibit adipocyte differentiation, possibly through suppression of C/EBPα and PPARγ expression (Sul, 2009). SREBPs are basic helix-loop-helix-leucine zipper transcription factors that play important roles in regulating expression of genes involved in the biosynthesis of cholesterol and fatty acids (Horton et al., 2002). Most of the lipogenic enzymes, such as acetyl-CoA carboxylaseα (ACCα ) and fatty acid synthase (FAS) are regulated by SREBP (Oh et al., 2003). Fatty acid-binding protein 4, an adipocyte differentiation marker, plays an important role in fatty acid transportation and metabolism, and its expression is also regulated by PPARγ (Damcott et al., 2004; Xu et al., 2006). The expression of FABP4 is increased dramatically as differentiation progresses (Billon et al., 2007), and contributes to hypertrophy by mediating the sequestration of fatty acids for TAG synthesis (Sarruf et al., 2005).

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markers for chicken preadipocyte differentiation, such as glycerol-3-phosphate dehydrogenase and citrate lyase (Ramsay and Rosebrough, 2003). In recent years, appetite-regulating peptides have emerged as factors that not only regulate food intake via the hypothalamus, but also act on the adipose tissue to regulate energy storage and expenditure. Neuropeptide Y (NPY) is a potent orexigenic peptide in both mammalian (Levine and Morley, 1984) and nonmammalian species (Kuenzel et al., 1987). In addition to appetite regulation, NPY plays other important roles in the body including regulation of energy homeostasis (White, 1993). Activation of NPY receptor 2 (NPYR2) enhances adipocyte proliferation and differentiation, and treatment with NPY can lead to obesity in mammalian species (Kuo et al., 2007). Consistent with this, NPYR2 knockout mice had reduced body weight gain and less adiposity (Shi et al., 2011). Although NPY receptors 1 (NPYR1) and 5 (NPYR5) are implicated in the effect of NPY on fat accumulation, there are fewer supporting studies compared to those focused on NPYR2 (Rosmaninho-Salgado et al., 2012; Zhang et al., 2014b). NPY also promotes adipogenesis in chicken adipose cells in vitro, which may involve slightly different mechanisms from those identified in mammals (Zhang et al., 2015; Shipp et al., 2016).

DIETARY FACTORS THAT AFFECT ADIPOGENESIS AND ADIPOSE TISSUE EXPANSION IN CHICKENS The remainder of this review will focus on dietary factors affecting adipogenesis in chickens (Table 1). While there was a review on the relationship of diet to adipose tissue development in chickens (Fouad and ElSenousey, 2014), this will focus on the molecular and cellular mechanisms underlying effects of dietary factors on the adipose tissue.

Lipid Source HORMONES THAT REGULATE ADIPOGENESIS In mammalian models, a glucocorticoid (dexamethasone), a phosphodiesterase inhibitor (3-isobutyl-lmethylxanthine (IBMX)) and insulin induce adipocyte differentiation in vitro, and are often included together in what is referred to as an “adipose differentiation cocktail” (Ailhaud, 1982; Pairault and Lasnier, 1987; Soret et al., 1999). However, the mixture of these 3 factors may not be sufficient to promote chicken preadipocyte differentiation (Matsubara et al., 2005). Dexamethasone is a strong inducer during the early stages of adipogenesis and directly enhances transcription of master regulators, such as PPARγ , C/EBPβ and C/EBPδ (Ramos et al., 1996; Gotoh et al., 1997). Porcine insulin increases the activity of known enzyme

At hatch, the chick transitions from the nourishment of a lipid-rich yolk to a carbohydrate- and protein-based diet, during which time there is dramatic morphological and functional development of the gastrointestinal tract (Uni et al., 2003; Noy and Uni, 2010). When chicks were fed a high-fat diet (9% vs 4.5% crude fat; diets supplemented with soybean oil) or high-protein diet (28% vs 18% crude protein) from hatch, carcass fat percentage did not differ at 7 d of age (Noy and Sklan, 2002). Absorption of fatty acids from dietary fat is considered to be efficient at hatch and because consumption of a high-fat diet was not accompanied by increased body fat deposition as seen in older chickens, it was suggested that mechanisms to enhance deposition of energy as adipose tissue are not yet in place during the first week posthatch (Noy and Sklan, 2002). This is in contrast to older female chickens (12 to 49 d of age)

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Table 1. Some factors affecting adipose tissue development in chickens. Factors Fat Sunflower oil Linseed oil Fatty acids Oleic acid Conjugated linoleic acid Polyunsaturated fatty acid Medium-chain fatty acid Carbohydrates Amino acids Arginine Lysine Methionine Other factors Soy isoflavones Betaine Probiotics

Mechanisms1

Citations

Hepatic FAS CPT I and L3HOAD in heart + Fatty acid β -oxidation -

Sanz, 1999 Sanz et al., 2000 Sanz et al., 2000

FABP4 and C/EBPβ PPARγ mRNA Fat synthesis Fatty acid oxidation + Not fully understood FAS + Hepatic malic enzyme Hepatic lipogenic enzyme Dietary amino acid imbalance Not fully understood

Regassa and Kim, 2013 Ramiah et al., 2014 Sanz et al., 2000

Unknown LPL and FAS mRNA Lipid synthesis Fatty acid catabolism +

Wang et al., 2015 Back et al., 1986 Mohiti-Asli et al., 2012 Wu et al., 2011 Nasr and Kheiri, 2012 Takahashi and Akiba, 1995 Xing et al., 2011 Homma and Shinohara, 2004

1 +, increased; -, decreased. Abbreviations: FAS, fatty acid synthase; CPT I, carnitine palmitoyltransferase I; L3HOAD, L-3-hydroxyacyl-CoA dehydrogenase; FABP4, fatty acid binding protein 4; C/EBPβ , CCAAT/enhancer binding protein-β ; PPARγ , peroxisome proliferator-activated receptor γ ; LPL, lipoprotein lipase; ACC, acetyl-CoA carboxylase.

where an increase in dietary fat (tallow or olive oil) from 6% to 10% was associated with increased abdominal fat (Crespo and Esteve-Garcia, 2001). In general, as the animal matures, the amount of body fat increases while muscle decreases, and the deposition of adipose tissue is influenced by the energy to protein ratio in the diet (Summers and Leeson, 1984; Perreault and Leeson, 1992). In addition to the energy density and crude fat percentage of the diet, the source of fat also affects body fat deposition. Chickens fed diets containing sunflower oil (predominately composed of unsaturated fatty acids) as the major source of supplemental fat had less abdominal fat than those fed diets supplemented with tallow or lard (greater proportion of saturated fatty acids) (Sanz, 1999). Inclusion of sunflower oil in the diet was associated with reduced plasma TAGs and FAS activity in the liver and enhanced carnitine palmitoyltransferase I and L-3-hydroxyacyl-CoA dehydrogenase activities in the heart, as compared to the physiology of birds that ate diets containing tallow (Sanz et al., 2000c), suggestive of enhanced rates of β oxidation in the heart and reduced lipogenesis in the liver. These results indicate that energy-demanding tissues such as skeletal muscle enhance their uptake of fat as an energy source from sunflower oil, preventing deposition as fat (Sanz et al., 2000c).

Fatty Acids The effects of dietary fat source on adipose tissue physiology may be due in part to the effects of individual fatty acids on metabolism. Fatty acids are ubiquitous biological molecules that besides providing energy and constituting cellular membranes, can also

function as mediators of adipocyte differentiation and metabolism in mammals (Gaillard et al., 1989; Amri et al., 1991). Fatty acids are important for the induction of chicken adipocyte differentiation, the effect associated with an increase in PPARγ gene expression (Matsubara et al., 2008). Fatty acids regulate gene transcription by serving as regulatory ligands for specific transcription factors or by being involved in intracellular metabolism, such as by serving as substrates for TAG synthesis, or as precursors for other biological molecules (Jump and Clarke, 1999). Fatty acids serve as PPAR ligands (Hertzel and Bernlohr, 1998; Sampath and Ntambi, 2004), which may partly explain why fatty acids and their derivatives have hormone-like effects. Thus, fatty acids can affect preadipocyte proliferation and differentiation by regulating transcription of specific genes and also by serving as substrate for the accelerated TAG synthesis that occurs during adipocyte maturation. The expression of C/EBPs, PPARs, and other adipose-specific genes is regulated by the presence of fatty acids during the early phase of adipocyte development in mammals (Azain, 2004) and birds (Matsubara et al., 2005). Because the liver is the main site of fatty acid synthesis in chickens, additional fatty acid supplementation may be required to promote differentiation of chicken adipocytes in culture (Matsubara et al., 2005). Oleic acid was an essential source of exogenous fatty acids for chicken adipocyte differentiation in vitro when fetal bovine serum was used instead of chicken serum to supplement the media (Matsubara et al., 2005). In one study, oleate alone (i.e., absence of differentiation cocktail) was able to stimulate lipid droplet formation in chicken preadipocytes (Shang et al., 2014). The same group also reported that oleate has the capacity to promote trans-differentiation of chicken fibroblasts into

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adipocyte-like cells (Liu et al., 2009). The adipogenesisinducing effect of oleic acid in laying hen adipocytes was explained by the corresponding increase in gene expression of FABP4 and C/EBPβ (Regassa and Kim, 2013; Regassa and Kim, 2015). Conjugated linoleic acid (CLA) is a mixture of mainly cis-9,trans-11 and trans-10,cis-12 fatty acid isomers. Many in vivo and in vitro studies showed that dietary CLA mediates cell growth, nutrient utilization and storage, and lipid metabolism in rodents and pigs, and that when fed to animals it partitions energy from fat to skeletal muscle growth (Pariza et al., 2001; Mersmann, 2002b). Total body fat was reduced in chickens fed 2 or 3% dietary CLA from 3 to 6 wk of age (Du and Ahn, 2002). In rats, the CLA-induced decrease in body fat mass was because of a decrease in adipocyte size, rather than adipocyte number (Azain et al., 2000). Dietary CLA also increases SFA and decreases monounsaturated fatty acid (MUFA) content in the abdominal fat of chickens, which most likely results from inhibiting the Δ-9 desaturase enzyme system that is responsible for SFA desaturation, converting SFA into MUFA (Chamruspollert and Sell, 1999). When polyunsaturated fatty acids (PUFAs) are supplemented in the diet, there is decreased abdominal fat (Crespo and Esteve-Garcia, 2001), fat in other depots (Crespo and Esteve-Garcia, 2002) and total body fat (Sanz et al., 2000a), compared to supplementation with saturated or monounsaturated fats. This may be explained by results from studies suggesting that PUFA suppress fat synthesis (Wilson et al., 1986; Blake and Clarke, 1990; Sanz et al., 2000b), and increase fatty acid oxidation (Shimomura et al., 1990; Cunnane and Anderson, 1997; Madsen et al., 1999), in mammals and birds. The majority of metabolic effects of fatty acids consumed are controlled at the level of gene transcription regulation, either indirectly or directly by nuclear hormone receptors such as PPARs (Wahli et al., 1995; Wahle et al., 2003). PUFA and CLA isomers act as ligands for PPARs (Xu et al., 1999; Mersmann, 2002a), and dietary CLA is associated with decreases in PPARγ mRNA abundance in chicken abdominal fat (Ramiah et al., 2014). However, a combination of a variety of long-chain fatty acids induced chick adipocyte differentiation by upregulating PPARγ mRNA and protein expression (Matsubara et al., 2008). Fatty acids with different structures may thus act on adipogenesis through different mechanisms. Compared to long-chain fatty acids (LCFAs), medium-chain fatty acids (MCFAs) are associated with decreased fat deposition in mammals due to faster metabolism and reduced storage in adipocytes (StOnge et al., 2003; Takeuchi et al., 2006). In chickens, MCFA supplementation may be more advantageous than LCFA in reducing abdominal and intermuscular fat (Wang et al., 2015). However, the specific mechanisms are not fully understood. Thus, both the degree of saturation and the chain length are associated with different metabolic functions of fatty acids in chickens.

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Dietary Carbohydrates The ACC is considered to be a rate-limiting step in the fatty acid synthesis pathway, catalyzing the ATPdependent carboxylation of acetyl-CoA to malonyl-CoA to donate carbon atoms for long-chain fatty acid synthesis (Brownsey and Denton, 1987). The activity of ACC also controls the rate of β -oxidation of fatty acids. In the liver of rats, ACC protein was diminished by fasting and increased following fasting and refeeding with a high carbohydrate diet (Evans and Witters, 1988; Bianchi et al., 1990). Feeding previously 24-hour fasted mice a high-carbohydrate, low-fat diet led to increased hepatic mature SREBP-1c expression that was 4- to 5-fold greater than non-fasted levels (Horton et al., 1998). In chickens, ACC mRNA and protein in the liver increased markedly after hatch in growing chicks (Takai et al., 1988). Many studies indicate that this developmental regulation in growing chicks is associated with changes in diet, from relatively high-fat, low-carbohydrate nutrition in chick embryos to relatively low-fat, high-carbohydrate nourishment in growing chicks (Volpe and Vagelos, 1976). Collectively, these results suggest that factors associated with fatty acid and lipid synthesis are up-regulated in the liver and adipose tissue of animals that consume a relatively high-carbohydrate, low-fat diet, reflecting the partitioning of energy from glucose to other physiological pathways besides direct oxidation.

Dietary Protein Dietary protein quantity profoundly affects animal growth and body composition. An increase in dietary protein from 20% to 33% was associated with decreased abdominal fat and enhanced body weight gain and breast muscle yield in 28-day-old commercial broilers (fed after d of hatch) (Temim et al., 2000). Consumption of a high-protein diet (23% vs 17% or 17% vs 13%) was associated with decreased abdominal fat and increased body weight and breast meat yield in chicks from lines selected for high and low abdominal fatness, compared with birds that were fed a low-protein diet for 9 or 7 wk posthatch (Alleman et al., 2000; Jlali et al., 2012). However, feeding diets with varying protein levels (from 18 to 28%) for the wk 1 posthatch did not alter fat deposition in 7-day-old broiler chicks (Noy and Sklan, 2002). Thus, similar to effects of dietary fat, dietary protein probably affects carcass quality of chickens more dramatically at a later age. Feeding a diet with increased dietary protein (17.4 vs. 14.5%) for 12 wk was associated with reduced hepatic malic enzyme activity and decreased abdominal fat weight and hepatic and plasma TAG concentrations in laying hens, suggesting that malic enzyme is important in regulating the rates of de novo fatty acid synthesis in the avian liver (Mohiti-Asli et al., 2012). Six and 24 h of consuming a high protein diet (40 vs 22%) decreased malic enzyme activity and total liver lipid

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content in 6- and 7-day-old chicks (Adams and Davis, 2001). The activity of hepatic malic enzyme may be correlated with rates of lipid synthesis, since it has been suggested that malic enzyme in addition to the dehydrogenases of the glucose monophosphate shunt may provide NADPH for lipogenesis in the liver (Fitch and Chaikoff, 1960; Lowenstein, 1961).

Amino acid Supplementation Depending on the genetic background and age, supplemental essential amino acids are provided in the poultry diet at varying concentrations. Amino acids exert various biological functions in addition to being an energy source or constituent of proteins. Several studies have evaluated effects of dietary amino acid supplementation on adipose tissue physiology of birds and mammals. Arginine is a protein constituent that acts as an insulin and growth hormone secretagogue, as well as a precursor for creatine, nitric oxide, and polyamine synthesis (Merimee et al., 1969; Bolea et al., 1997). When arginine was supplemented in the drinking water at 1.51% for 12 wk, relative weights of specific muscles and percentage of brown fat were increased while white adipose tissue pad weights were reduced by 30%, compared with control rats that were provided 2.55% Lalanine (isonitrogenous control) (Jobgen et al., 2009). One of the explanations was that arginine-associated increases in nitric oxide production led to increased mitochondrial biogenesis, which in turn generated more oxidative activity and heat production. Consistent with this hypothesis, Tan et al. (2011) showed that in pigs that consumed diets supplemented with 1.0% arginine (in a diet that met all nutrient requirements) there was increased skeletal muscle mass, decreased adipose tissue, and increased lipid content in the longissimus dorsi. The expression of FAS mRNA in muscle and HSL mRNA in adipose tissue was increased, whereas LPL, glucose transporter-4 and ACC-α mRNAs were decreased in adipose tissue, as compared with control pigs (2.05% L-alanine) (Tan et al., 2011). These results from rat and pig studies indicate that dietary arginine has the capacity to shift nutrient partitioning whereby lipogenesis is favored in muscle while lipolysis is enhanced in adipose tissue. Birds are unable to synthesize arginine because the urea cycle is not functional, with uric acid being the primary form of nitrogen excretion in avians (Fernandes et al., 2009). At an early age, chicks have a markedly acute need for dietary arginine as it is also possibly involved in immune system development and defending against early microbial challenges (Corzo and Kidd, 2003). The effect of arginine supplementation on fat deposition has been inconsistent in chickens. Mendes et al. (1997) reported that from 21 to 42 d of age increasing dietary arginine: lysine ratios (from 1.1:1 to 1.4:1) reduced abdominal fat content (Mendes et al., 1997). In 6-week-old ducks that were fed 1% arginine for the first

42 d posthatch, there was reduced carcass fat deposition and smaller abdominal adipocytes, which authors attributed to a decrease in hepatic lipogenic enzyme activity, suggesting that there were fewer circulating fatty acids available for lipid deposition in adipose tissue (Wu et al., 2011). However, 0.4% arginine supplementation (in a diet that met all nutrient requirements) only during the starting phase (1 to 21 d) did not affect abdominal fat deposition in 6-week-old chickens (Fernandes et al., 2009). The lack of effect of dietary supplemental arginine could be related to the duration of feeding or inclusion rate of arginine in the diets. Lysine is one of the key amino acids for protein synthesis and muscle deposition. It is also important for immune system function in response to infection, a lysine deficiency hindering the antibody response and cellmediated immunity in chickens (Geraert and Mercier, 2010). Dietary lysine levels also affect carcass composition. In 6-week-old chickens that were fed diets with lysine levels 10% above or below the requirement levels, abdominal fat deposition was significantly increased by both diets, which could be associated with a dietary amino acid imbalance, resulting in excess amino acids being catabolized, carbons then used as gluconeogenic substrate and resulting glucose catabolized and converted into fatty acids, and deposited into adipose tissue (Nasr and Kheiri, 2012). In poultry diets, methionine is usually the first limiting amino acid. Five-week-old chickens fed 0.60% methionine (total methionine level in the diet) for 4 wk had reduced abdominal fat compared with chickens fed 0.40% methionine (both met methionine requirements) (Opoola et al., 2013). However, when a dietary methionine deficiency was imposed, body fat deposition was increased in broilers at 6 and 8 wk of age (Moran, 1994).

Other Dietary Factors Soy isoflavones are reported to be involved in the regulation of physiological activities in a variety of tissues or organs, including adipose tissue, liver and skeletal muscle (Ørgaard and Jensen, 2008; Xiao, 2008). Takahashi and Ide (2008) reported that dietary supplementation of 0.5 or 4 g/kg diet soy isoflavones increased fatty acid oxidation in rat liver by up-regulating PPARγ and uncoupling protein expression (Takahashi and Ide, 2008). In chickens, dietary soy isoflavone supplementation (0.70 and 1.73 g/kg diet vs 0.35 g/kg diet in the starter diet) was associated with increased breast muscle yield but did not affect abdominal fat percentage of body weight in 52-day-old broiler chickens (Payne et al., 2001). As a trimethyl derivative of glycine, betaine may decrease the dietary requirement for other methyl donors including choline and methionine. Dietary supplementation of betaine reduced abdominal fat deposition in broiler chickens (Esteve-Garcia and Mack, 2000; McDevitt et al., 2000). Xing et al. (2011) hypothesized

ADIPOSE TISSUE DEVELOPMENT IN CHICKENS

that dietary supplementation of 0.1% betaine decreases abdominal fat accumulation through a down-regulation in the expression of LPL and FAS mRNA, as observed in 66-day-old broilers (Xing et al., 2011). Probiotics have been used to prevent overgrowth of undesirable microbes in the gastrointestinal tract and favor the establishment of benign bacterial species. Dietary supplementation of some strains of probiotics (Bacillus subtilis or Bacillus cereus toyoi) decreased abdominal fat accumulation in chickens (Santoso et al., 1995) and Japanese quail (Homma and Shinohara, 2004), which may be partially explained by decreased ACC activity in the liver (Homma and Shinohara, 2004).

CONCLUSIONS AND IMPLICATIONS Adipose tissue development is mediated by a variety of factors, including nutritional, hormonal and transcription factors. There are a variety of transcription factors that regulate adipogenesis and among them PPARγ is considered to be the “master” regulator. There have been advancements in understanding adipose tissue development in chickens, although the molecular and cellular mechanisms are not fully elucidated. Feed constitutes a large proportion of total broiler production costs, thus, maximizing the efficiency of feed utilization is important from an economical perspective. Understanding the cellular pathways governing adipose tissue development and how these pathways are influenced by dietary factors may contribute to practical strategies to improve poultry production efficiency and provide novel insights for biomedical research. We reviewed papers describing how altering the amount and composition of fat and protein in the diet affects abdominal fat accumulation in broilers. There is evidence to suggest that replacing SFAs with PUFA, or supplementing various additives in broiler breeder diets may reduce abdominal fat deposition thus improving reproductive performance. Broiler chickens have been selected for rapid growth, and for broiler breeders egg production is inversely proportional to body weight. Thus, nutritional manipulations may improve the fitness and welfare of broiler chickens by increasing reproductive effectiveness and reducing the incidence of musculoskeletal diseases, metabolic disorders and mortality. Such practices will also improve the welfare of broiler breeders as dedicated programs of feed restriction are applied to maintain proper body weight. In conclusion, understanding how diet composition affects adipose tissue development has many economical and health and welfare implications for poultry production.

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