Transcript Age and Adipocytes - Iran Obesity Society Official Homepage

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.
Anatomical distribution of adipose tissue
Subcutaneous adipose tissue :
- abdominal
- femoral
Intraabdominal adipose tissue :
- visceral (mesenteric and omental)
-retroperitoneal (perirenal and
perigonadic)
Other depots :
- intra and intermuscular
- perivascular
- epicardiac
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 retroorbital 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
Hypoplasia/
Hypotrophy:
Lipodystrophy
Diabetes
Dyslipidaemia
Fat Cell Mass
Eufunction
Longevity
Fertility
Glucose/Energy Homeostasis
Intact Immune System
Cardioprotection
Hyperplasia/
Hypertrophy:
Obesity
Diabetes
Dyslipidaemia
Cardiovascular Morbidity
Hypertonus
Cancer
Dysfunction:
Adiposopathy
• 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
Adipose tissue development : beyond adipocyte
differentiation
Mature Preadipocytes
adipocytes
Endothelial
cells
Mature
adipocytes
ADIPOCYTE
HYPERTROPHY
& HYPERPLASIA
ANGIOGENESIS
INFLAMMATION
Macrophages Preadipocytes
• 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)
Transcriptional control of adipocyte differentiation
SREBP1c / ADD1
PPAR b
RXRa
PPAR g
C/EBP b/d
C/EBP a
Wnt signaling
GATA 2 & 3
proliferation
differentiation
fat cell-specific
gene
expression
J. Lipid Res., 2002, 43, 835-860
• 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. 2007 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 insulinsensitive 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 adipocytelike 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
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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