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VOLUME 13 NUMBER 2 • DECEMBER 2016
REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
Central adiposity, ectopic fat deposition and obesity-
related co-morbidities
‘Not all fat is created equal’ may be the new dogma in obesity
research, with many studies reporting that the pathological effects
of excessive adiposity are dependent not only on the quantity of
fat, but on the distribution of the fat mass. The adipose tissue
surrounding the major abdominal organs, the visceral fat, is thought
to be the principal adipose depot involved in the aetiology of obesity-
related disorders, with the subcutaneous fat depot playing a less
prominent role.
10
Closer scrutiny of adipocytes isolated from these
two fat depots has corroborated this view and shown fundamental
metabolic differences as well as a higher production from visceral
adipocytes of adipose tissue-derived cytokines (adipokines), which
may play an important role in the aetiology of many obesity-related
diseases.
11
It has been proposed that the rate of lipid uptake is greater
in the subcutaneous than the visceral adipose tissue depot
until the former site approaches its limit for lipid storage, when
triglyceride uptake into the visceral depot predominates.
12,13
Lipid
accumulation in obesity promotes both adipocyte hyperplasia
and hypertrophy,
14,15
with storage mainly occurring in pre-existing
adipocytes. As hypertrophy progresses, the storage capacity of
the cells in subcutaneous adipose tissue becomes limiting and
lipids that are not readily accumulated are shunted to the visceral
stores. Excessive fat accumulation in the visceral stores leads to the
secretion of free fatty acids into the portal vein, which, with the
secretion of pro-inflammatory adipokines, leads to hepatic insulin
resistance and aberrant accumulation of lipids in hepatocytes and
the resultant hepatic steatosis.
16
In obese individuals, the inadequate lipid storage capacity of the
body’s adipose tissue depots leads to ectopic fat deposition not
only in the liver but in other organs such as skeletal muscle and
the insulin secreting b-cells of the pancreas. It has been suggested
that this ectopic fat deposition may play an important role in the
aetiology of both insulin resistance and
β
-cell failure.
17
Furthermore,
in obesity, increased fat deposition has also been noted peri-
vascularly and peri-cardially and within myocytes.
18
It has been
suggested that this may contribute to vascular stiffness, cardiac
dysfunction, hypertension, atherosclerosis and sodium retention,
which are all characteristics of the cardiovascular disease observed
in obese subjects.
18
Adipose tissue, a paracrine and endocrine organ
Adipose tissue is no longer just seen as a fat store, but is considered
a true secretory tissue, with differences in secretion underpinning
the greater pathogenicity of visceral than subcutaneous fat masses.
Adipocytes are known to secrete pro-inflammatory cytokines such
as TNF
α
and IL-6, which in conjunction with elevated free fatty acids
(FFAs), promote insulin resistance.
11
These cytokines are elevated
in obesity and have been proposed to act in an autocrine loop,
inhibiting the adipocyte hyperplastic response, which in turn leads
to hypertrophy and further secretion of FFAs and pro-inflammatory
cytokines.
Adipocytes produce a multitude of secreted peptides other
than pro-inflammatory cytokines that have been linked to some
of the obesity-related co-morbidities. Many of these molecules,
such as plasminogen activation inhibitor 1 (PAI-1), angiotensinogen
(AGT), monocyte chemo-attractant protein 1 (MCP-1) and resistin,
have effects on vascular function. Plasminogen activation
inhibitor 1 inhibits plasminogen activation and leads to fibrinolysis
and a pro-thrombotic state.
19,20
PAI-1 is secreted more by visceral
than subcutaneous fat
21
and is also a risk factor for coronary
artery disease (CAD),
22
whereas angiotensinogen has been
implicated in the aetiology of hypertension and is upregulated
in obesity,
23,24
with production being higher in visceral fat.
25
Furthermore, angiotensinogen is the precursor of angiotensin II of
the vasoconstriction renin–angiotensin system and may be a causal
agent for the hypertension seen during obesity.
26
Monocyte chemo-attractant protein 1 is also secreted
predominantly from the visceral depot, is overproduced during
obesity and participates in the recruitment of macrophages and
monocytes into the arterial cell wall. As this recruitment may lead
to atherosclerosis, MCP-1 was measured in patients with or without
CAD, and it was found to be elevated in the former group.
27
Adipocytes also secrete resistin, which stimulates inflammatory
cytokine production, as well as decreasing endothelial cell adhesion
molecule (iCAM-1, vCAM-1, Ccl-2) production, which may promote
atherosclerosis.
28
The role of resistin in insulin resistance is still
unclear.
29,30
Adipose tissue also secretes other peptides that have effects
peripherally and centrally. The most investigated of these is leptin,
a satiety factor which was first characterised in a rodent model
of monogenic obesity, the ob/ob mouse.
31
Since the isolation and
characterisation of leptin (from the Greek leptos: thin), adipose
tissue has been viewed as a true endocrine organ. Leptin is
secreted by adipocytes and modulates food intake by suppressing
orexigenic peptides (Agouti-related peptide and neuropeptide Y)
and upregulates anorexigenic peptides (corticotropin-releasing
hormone and
α
-melanocyte stimulating hormone) in the brain.
32
It
also stimulates fatty acid oxidation and prevents lipid accumulation
in adipose tissue.
33,34
This forms a negative feedback mechanism,
where increased fat mass produces more leptin, which reduces
food intake, inhibiting further adipose expansion and limiting leptin
expression. It was initially thought that this feedback loop could be
used to inhibit food intake in the obese, but clinical trials of leptin
analogues had little success, because endogenous leptin has since
been found to be elevated in the obese, who often exhibit leptin
resistance.
35
The adipokine has since been attributed to being a
signal for energy deficiency, rather than a signal to lose weight,
as excessive weight loss will result in decreased leptin levels and a
consequential increase in food intake.
36,37
Since the characterisation of leptin, many other adipokines have
been discovered, such as apelin, visfatin, chemerin and vaspin, with
adiponectin being the most fully studied. Adiponectin is copiously
secreted from mature adipocytes,
38-40
with expression negatively
correlating with body mass index (BMI).
41,42
Consequently, lean
subjects have high levels, whereas obese subjects have low plasma
levels. Decreased expression of adiponectin is observed in a number
of obesity-related co-morbidities such as type 2 diabetes,
43,44
the
metabolic syndrome,
45,46
non-alcoholic steatohepatitis
16
and
CAD.
47,48
It has also been found that the protein is anti-diabetic,
increasing insulin sensitivity, glucose uptake and fat oxidation, as
well as suppressing hepatic glucose output.
49-51
The protein may
also alter basal insulin secretion
52
and modulate satiety, increasing
food intake and suppressing energy expenditure when fasting, but
surprisingly having opposite effects after refeeding.
53
It is also anti-
atherogenic
47,54
and anti-inflammatory.
55
Whereas adiponectin decreases during obesity, there are other
glucose-lowering adipokines that correlate positively with BMI.