Ontogeny Adipose Tissue

Gary J. Hausman

United States Department of Agriculture, Agricultural Research Service, Athens, Georgia, U.S.A. D. B. Hausman

University of Georgia, Athens, Georgia, U.S.A.

INTRODUCTION

Adipose tissue, now considered an endocrine organ, secretes or expresses many potential endocrine factors, including leptin and insulin-like growth factor (IGF) system proteins. Therefore, the structrual and functional aspects of adipose tissue ontogeny are important to the growing and mature animal.

FETAL AND NEONATAL DEVELOPMENT

Fat cell development commences by midgestation and is characterized by the appearance of a number of fat cell clusters, or primitive organs, which subsequently increase in number and size throughout fetal development (Table 1).[1-3] Primitive fat organs are vascular structures in presumptive adipose tissue with few or no fat cells (Fig. 1; Table 1). Fetal adipocyte development is spatially and temporally related to capillary development.1-2-1 Although angiogenesis appears to be linked to adipo-genesis, the major regulators of angiogenesis have not been examined in meat animal adipose tissue (Table 2).

Subcutaneous (SQ) depots develop before internal depots in chickens, cattle, and sheep, whereas the middle SQ layer and internal depots develop concurrently in pigs. Subcutaneous adipose tissue layers are established at the onset of adipose development and have distinct fetal and postnatal developmental patterns.[1,5]

Brown adipose tissue (BAT) is responsible, in part, for nonshivering thermogenesis in the neonate. Brown adipocytes contain more elaborate and differentiated mitochondria (Table 1)[4] than multilocular adipocytes in developing white adipose tissue (WAT; Table 1). BAT is characterized by expression of uncoupling protein (UCP-1), a mitochondrial transport protein responsible for BAT heat production. Leptin gene expression effectively marks white adipocytes since it is positively correlated with the unilocular cell morphology but inversely related to UCP-1 expression. Leptin influences many physiological processes and is primarily synthesized and secreted by WAT. BAT has not been detected in pigs and chickens but is present in neonatal ruminants and, except for goats, is generally found only in internal fat depots. Bovine SQ originates as BAT to a degree but soon converts to WAT. At birth, sheep and cattle BAT and WAT have a mature morphology since these tissues are virtually filled with adipocytes (Table 1). BAT rapidly transforms to WAT in neonatal ruminants during the neonatal period (Table 1).

POSTNATAL DEVELOPMENT

WAT predominates in postnatal animals and adipocyte development is depot- and species-dependent (Table 3).[5-7] Adipocytes in internal depots are larger than those in the intramuscular depot, and adipocyte hypertrophy is largely responsible for fat accretion of most depots (Table 3). Generally, fat cell hypertrophy is associated with increased leptin gene expression. In the SQ depot, leptin expression responds to fasting and hormones associated with the onset of puberty.[8,9] Leptin expression traits distinguish adipose depots in sheep and cattle (Table 3).

ADIPOSE TISSUE EXPRESSION OF TRANSCRIPTION, METABOLIC, AND REGULATORY FACTORS

Adipose cell differentiation is accompanied by transcrip-tional activation of genes by several groups of transcription factor proteins: PPARg, C/EBPs and ADDI/SREBP-1 (Table 2). C/EBPa, p, and PPARg were expressed early and throughout fetal pig adipose tissue development.1-3-1 The expression levels of several transcription factors and associated adipogenic genes increase neonatally and expression of the stearoyl coenzyme A desaturase (SCD) gene rapidly increases postnatally in several species (Table 2).

HORMONAL REGULATION OF ADIPOSE TISSUE DEVELOPMENT AND METABOLISM

Fetal hypophysectomy (hypox) increases SQ adipose tissue accretion in fetal sheep and pigs, and increases

Table 1 Characteristics of fetal and neonatal adipose tissue development

Fetal

Key developmental traits

Mode of accretion or expansion Molecular and ultrastructural markers Late fetal tissue and adipocyte morphology

Neonatal Tissue and adipocyte morphology

Mode of accretion or expansion

Accretion or expansion rate Molecular and ultrastructural markers

Depot dependent development of primitive fat organs and structural differentiation of presumptive fat tissue C and S: hyperplasia and hypertrophy; P: hyperplasia with less hypertrophy Leptin; few and simple mitochondria

Moderately vascular, mature (C,S) or immature (P) tissue with either unilocular and multilocular cells (C,S) or smaller multilocular cells (P)

Mature tissue with unilocular cells (C, P) or multilocular and unilocular cells (S)

Depot dependent hyperplasia and hypertrophy

Rapid

Expression of leptin, transcription factors, and lipogenic enzymes

Depot dependent development of primitive fat organs

Hyperplasia and hypertrophy

UCP 1; mitochondria proliferation and differentiation

Very vascular, mature tissue with unilocular and multilocular cells

Mature tissue with unilocular cells (C) or cells transforming from multilocular to unilocular (S) Hypertrophy

Relatively slow

BAT to WAT conversion : Decreased UCP 1 expression and structural and functional mitochondrial degradation

Abbreviations: UCP 1 uncoupling protein, WAT white adipose tissue, BAT brown adipose tissue.

Fig. 1 Phosphatase histochemistry in cryostat sections of fetal perirenal adipose tissue from 70 day (A), 90 day (B) and 105 day (C, D) fetal pigs. Note that phosphatase reactivity is limited in arterioles (arrows) in perirenal tissue at 70 days (A), whereas more extensive phosphatase reactivity indicates that arteriolar differentiation (arrows) has clearly progressed by 90 (B) and 105 days (C, D). Areas within perirenal tissue at 90 days (B, arrowheads) can be considered primitive fat organs since there are few to no fat cells but the areas are otherwise morphologically similar to adipocyte filled areas (a) of adipose tissue at 105 days (C). A, B, C x 300; D x 150.

Fig. 1 Phosphatase histochemistry in cryostat sections of fetal perirenal adipose tissue from 70 day (A), 90 day (B) and 105 day (C, D) fetal pigs. Note that phosphatase reactivity is limited in arterioles (arrows) in perirenal tissue at 70 days (A), whereas more extensive phosphatase reactivity indicates that arteriolar differentiation (arrows) has clearly progressed by 90 (B) and 105 days (C, D). Areas within perirenal tissue at 90 days (B, arrowheads) can be considered primitive fat organs since there are few to no fat cells but the areas are otherwise morphologically similar to adipocyte filled areas (a) of adipose tissue at 105 days (C). A, B, C x 300; D x 150.

Table 2 Collective reports of genes and proteins expressed during adipose tissue ontogeny

Regulatory

Metabolism

Transcription factors

Fetal

BAT cattle

BAT and WAT sheep and goats Neonatal WAT pigs (P) and cattle (C)

BAT cattle BAT and WAT sheep and goats Postnatal Pig WAT

Cattle WAT

Sheep WAT

P: leptin,OBLR, IGFBP 1, 2, 3, 4, 5, IGF I, II, TGF ß, adipsin; C:UCP 1 UCP 1, ß 13 ARs

P: leptin,UCP 2, 3, GHR, IGF I, II ;C :PREF1, ß 1 3 ARs. UCP 1,a ß 13 ARs Leptin, UCP 1,a GR, ANG II receptors 1, 2

Leptin, OBLR, EGF IGFBP 1, 3, bFGF, HGF, GHR, IGF I, II, IGF IR, ß 13 ARs, adipsin Leptin, Dlk 1 C 2, PREF1,a UCP 1,a IGF 1,NAT1, TNFa, heat shock 70 kDa protein Leptin, OBRL, UCP 2

Cytochrome c oxidase, ADP/ ATP carrier

GAPDH,VDAC, ADP/ATP carrier, cytochrome c oxidase

Cytochrome c oxidase, ADP/ ATP carrier 11 b HSD 1, 2, cytochrome c oxidase, ADP/ATP carrier, GLUT 4

SCD, GLUT 4, HSL GLUT 1, LPL, ACC, ATP citrate lyase, VDAC, GDH, FAS

ADD1, SREBP 1, SREBP 2, PPARg, PPARa, C/EBPa, C/EBP ß

PPARg 1, 2

PPARg

Abbreviations: ADD1 adipocyte determination and differentiation dependent factor 1, PPAR peroxisome proliferator activated receptor, C/ EBP CCAAT enhancing binding protein, SREBP sterol regulatory element binding protein, FAS fatty acid synthase, ACO acyl CoA oxidase, EGF epidermal growth factor, bFGF basic fibroblast growth factor, TGF transforming growth factor, TNF tumor necrosis factor, HGF hepatocyte growth factor, GLUT glucose transport protein, IGFBP insulin like growth factor binding protein, IGF insulin like growth factor, IGF 1R IGF 1 receptor, GHR growth hormone receptor, OBR long form leptin receptor, HSL hormone sensitive lipase, LPL lipoprotein lipase, UCP uncoupling protein, 11 ß HSD 12 11 beta hydroxysteroid dehydrogenase, SCD stearoyl coenzyme A desaturase, ME malic enzyme, ß ARs beta adrenergic receptors, PREF1 preadipocyte factor 1, GDH glutamate dehydrogenase, GAPDH glyceraldehyde 3 phosphate dehydrogenase, aP2 fatty acid binding protein, ACC acetyl CoA carboxylase, ANG II angiotensin, VDAC voltage dependent anion channel, and NAT1 novel APOBEC 1 target 1.

'Undetectable. Additional genes/proteins reported: Postnatal pig adipose; low density lipoprotein receptor, low density lipoprotein related protein and high density lipoprotein binding protein; postnatal cattle WAT type III collagen and ribosomal proteins; fetal pig adipose laminin and type IV collagen.

Table 3 Characteristics of postnatal adipose tissue development

Postnatal depots

Internal

Subcutaneous

Intramuscular/ intermuscular

Adipocyte size

Largest

Intermediate

Smallest

Mode of accretion

Early: hyperplasia and

Early: hyperplasia and

Primarily hyperplasia with

or expansion

hypertrophy; later: primarily

hypertrophy; later: hypertrophy

little hypertrophy

hypertrophy

and species dependent hyperplasia

Accretion and

Species dependent

Dependent on location, layer

Slow

accretion rate

and species

Lipogenesis

Intermediate

Highest

Lowest

Leptin gene

Omental: moderate and

High to moderate and

Very low and not changed

expression basal

increased by fasting;

increased by fasting

by fasting

and response to fasting

Perirenal: species dependent

fat cell size and lipogenesis in fetal pig adipose tissue. Hormone-sensitive adipogenesis begins on approximately day 70 of fetal life.[1]

Hydrocortisone and thyroxine (T4) are critical for cellular and vascular development in fetal pig adipose tissue. In contrast, T3 and cortisol are critical for establishing BAT functionality, including UCP protein expression, in fetal sheep. Growth hormone (GH) decreases lipid deposition in fetal sheep and pigs and reduces fat cell size in fetal pigs.

Adipose tissue IGF-1 and IGFBPs mediate chronic hormone effects on adipose development in fetal, neonatal, and postnatal animals, and influence the onset of fetal pig SQ adipocyte development (Table 2).[10] Expression and secretion of IGF-1 and IGFBPs by adipose tissue increase with fetal age, and many components of the IGF-GH system are expressed by postnatal pig adipose tissue (Table 2).

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