Adipose Tissue and Age M.J. Hosseinzadeh (MD, PhD) School of Public Health and Institute of Public Health Research Tehran University of Medical Sciences

Fat mass and tissue distribution change dramatically throughout life.

Subcutaneous adipose tissue : - abdominal - femoral Intraabdominal adipose tissue : - visceral (mesenteric and omental) -retroperitoneal (perirenal and perigonadic) Other depots : - intra and intermuscular - perivascular - epicardiac Anatomical distribution of adipose tissue Different physiological and pathogenic roles of the fat depots

Middle or early old age (40–70 years) –Peak of fat mass Advanced old age (> 70 years) –a substantial decline, with fat tissue dysfunction and redistribution to muscle, bone marrow, liver and other tissues

Cartwright et al. 2007

Association of Age-related Fat Infiltration In bone reduced mineral density In muscle Development of insulin resistance Glucose intolerance Decreased functional capacity

In old age, there is less fat where it should be and more fat where it should not be, with potential clinical consequences.

the observed decrease in total body fat with old age does not coincide with a decline in percent body fat, which may remain constant or increase

Increasing age: Loss of retro-orbital and peripheral subcutaneous fat –Loss of fat from retro- orbital depots causes a sunken appearance to the eyes Preserve of visceral fat

Triceps skinfold thickness decreases after middle age particularly after age 75 Loss of subcutaneous fat predisposes to development of –pressure sore –thermal instability –cosmetic changes

high ratio of central to peripheral fat is associated with insulin resistance and increased risk of atherosclerosis and diabetes, even in lean subjects

Depot-specific changes in fat tissue function with aging may contribute to development of age-related metabolic disorders

Loss of fat tissue can also result in glucose intolerance potentially contributing to the paradoxical development of type II diabetes in very old, lean patients.

Adipose tissue plays a central role in maintaining whole body lipid and glucose homeostasis

Fat Cell Functions Insulin Sensitivity Thermogenesis Hormone Secretion

Dysfunction: Adiposopathy Eufunction Fat Cell Mass Hyperplasia/ Hypertrophy: Obesity Hypoplasia/ Hypotrophy: Lipodystrophy Fertility Glucose/Energy Homeostasis Longevity Intact Immune System Diabetes Cardiovascular Morbidity Diabetes Dyslipidaemia Cancer Cardioprotection DyslipidaemiaHypertonus

White adipocytes –store excess lipid –protect other tissues from toxic accumulation of lipids –Secretion of hormones affecting whole body insulin sensitivity.

Most cell dynamic research on aging has been focused on effects of aging on adipocyte replication. Less is known about effects of aging on the capacity of cells to acquire specialized function through differentiation

Adipocytes convert circulating cytotoxic free fatty acids into less damaging neutral triglycerides, thereby protecting other tissues from their lipotoxicity

Age-dependent lipotoxicity is related to a decrease in adipose tissue capacity to store free fatty acids

Because fat cell responsiveness to lipolytic agents decreases with increasing age declining body weight, fat mass, percent body fat, and fat cell size may be principally related to reduced capacity for lipid accumulation.

Fat cell size and number are related to –insulin sensitivity –glucose and fatty acid uptake –cytokine release Any changes in function and cellular composition of fat tissue might lead to changes in metabolic state and subsequent clinical complications

The age-related decline in fat depot size is a result of decreased adipocyte size and not a decrease in cell number New cells appear to be formed throughout the lifespan and fat cell number remains constant or increases in old age

Preadipocytes are a substantial component of fat tissue, accounting for 15 to 50% of all cells

ADIPOCYTE HYPERTROPHY & HYPERPLASIA ANGIOGENESIS INFLAMMATION Macrophages Mature adipocytes Preadipocytes Endothelial cells Mature adipocytes Preadipocytes Adipose tissue development : beyond adipocyte differentiation

Preadipocytes cultured from old animals demonstrate a decrease in –lipid accumulation –lipogenic enzyme activities –changes in differentiation-dependent gene expression

The same age-related changes are evident in colonies derived from single cells after several weeks ex vivo

These findings support the hypothesis that inherent properties of preadipocytes contribute to changes in growth and function of adipose tissue with age.

With aging a decrease in preadipocyte removal through differentiation into fat cells would be predicted to cause an increase in preadipocyte number.

Preadipocyte capacity for lipid accumulation declines with age Differentiating preadipocytes isolated from young (3 month old), middle-aged (17 months), and old (24 months) Fischer 344 rat epididymal depots

Adipose tissue growth results from two processes: Hyperplasia –the increase in number of adipocytes that develop from precursor cells Hypertrophy –the growth of individual fat cells due to incorporation of triglycerides

White adipose tissue

Adipogenesis is closely correlated with obesity and several obesity-related diseases, including –type 2 diabetes mellitus –cardiovascular disease –Hypertension –Hypercholesterolemia –Asthma –certain forms of cancer

Adipogenesis is the process by which fibroblastic preadipocyte precursors are converted into fat laden adipocytes. This process is regulated by external signals impacting on the preadipocytes as well as by an intricate network of signals and transcriptional regulators in the cells.

Preadipocyte differentiation is initiated or promoted by exposure of the preadipocytes to: –Nutrients –Hormonal effectors insulin glucocorticoids IGF-1 –Paracrine and autocrine effectors free fatty acids cyclic AMP

Adipogenesis

Adipogenesis is under the control of two transcription factors: CCAAT/enhancer binding protein α (C/EBPα) peroxisome proliferator-activated receptor γ (PPARγ)

proliferation fat cell-specific gene expression differentiation Transcriptional control of adipocyte differentiation Wnt signaling GATA 2 & 3 SREBP1c / ADD1 C/EBP  /  PPAR  C/EBP  RXR  PPAR  J. Lipid Res., 2002, 43,

Currently PPARγ is universally accepted as the master regulator that is necessary and sufficient to induce adipogenesis as no known factor can induce adipogenesis without PPARγ.

Researchers at the University of Central Florida have now discovered that monocyte chemotactic protein-1 (MCP-1)-induced protein (MCPIP), can trigger adipogenesis without involvement of PPARγ. »Younce et al. JBC Papers in Press. Published on August 7, 2009

MCP-1 was found to be produced, and MCPIP to be induced, before induction of PPARγ or other transcription factors in fibroblasts undergoing differentiation into adipocytes

C/EBPα and PPARγ are involved in transcriptionally transactivating adipose-specific genes, including –adipocyte-specific fatty acid binding protein (aP2 or fatty acid binding protein 4) –Adiponectin –fatty acid synthase –Leptin –glucose-specific transporter 4 (GLUT4) resulting in acquisition and maintenance of the fat cell phenotype

C/EBP regulates expression of key genes necessary for maintaining the fat cell phenotype Thus C/EBP is a "bottleneck" in the chain of events beginning with activation of preadipocyte differentiation and ending with the appearance and maintenance of functional fat cells.

Molecular mechanisms of age-related decreases in adipogenesis Exp Gerontol. Author manuscript; available in PMC 2008 June 1 Published in final edited form as: Exp Gerontol June; 42(6): 463–471.

Expression of C/EBPα, C/EBPδ, and PPARγ is substantially lower in differentiating preadipocytes isolated from old than from young rats

Overexpression of C/EBPα in preadipocytes from old rats restores capacity to accumulate lipid and acquire the fat cell phenotype, implying that there are changes with aging in mechanisms controlling differentiation upstream of these adipogenic transcription factors.

Therefore, an important change in the differentiation process with aging is the inability to maintain adequate levels of these key adipogenic regulators

changes in expression of the adipogenic regulators C/EBPα, C/EBPβ -LIP, and C/EBPδ contribute to blunted differentiation with aging.

The declines in adipogenic transcription factor expression and activity would be expected to influence the function of the adipocytes Continued activation of downstream target genes is required for maintenance of the normal adipocyte phenotype.

For example, reduced C/EBPα expression in adipocytes contributes to impaired glucose tolerance through impairing insulin- sensitive glucose transporter 4 (GLUT4) expression

Although intervening to alter expression of such proteins may not affect the underlying process causing senescence itself, but it could be feasible to restore specific functions to senescent cells through interventions.

Genes downstream of PPARγ, including aP2, carnitine palmitoyl transferase-1 (CPT1), and PPARγ co-activator 1α (PGC1α), are involved in regulating the pathways of fatty acid handling and mitochondrial function

The expression and activity of PGC1α declines with age in various tissues, causing a shift from fuel oxidation to storage with accumulation of lipotoxic fatty acids, which has been associated with insulin resistance and diabetes

Changes with age in lineage-specific transcription factors in bone (Moerman et al., 2004) and muscle (Lees et al., 2006) also lead to dysdifferentiation of their respective precursor cells

TNFα increases in fat tissue with age from –macrophages –preadipocytes

TNFα impacts adipose tissue –By interfering with preadipocyte differentiation –Causes lipolysis decreased fat cell size reduced insulin responsiveness

The effects of TNFα on preadipocytes appear to be fat depot-dependent TNFα inhibits C/EBPα and PPARγ expression and activity in differentiating preadipocytes Thus TNFα inhibits adipogenesis through multiple mechanisms.

more extensive replicative history and greater relative decline in capacity for adipogenesis, in subcutaneous compared to omental preadipocytes Resulted to earlier loss of subcutaneous than visceral fat with aging,

Dysdifferentiation of mesenchymal progenitors into mesenchymal adipocyte- like default (or MAD) cells in muscle, marrow, fat tissue, and elsewhere, could result from age-associated stress response pathway activation

Summary Aging is associated with –Changes in fat depot sizes –decreased adipocyte size –impaired adipose tissue function –Changes in cell dynamics of the fat cell progenitor pool –Decline capacities of preadipocytes for replication, differentiation, and resistance to apoptosis –increased fat tissue inflammatory cytokine generation