Fullness of Fat Storage Capacity: An Alternative to Adipocyte Insulin
John M. Poothullil, MD, FRCP
Brazosport Memorial Hospital
201 Oak Drive South, #106
Lake Jackson, TX 77566
adipocyte insulin resistance, insulin resistance, obesity, type 2 diabetes, fat
Obesity and type 2 diabetes are
considered to be insulin-resistant states. Insulin resistance is diagnosed when
glucose transport is reduced and hepatic glucose production is increased in the
presence of normal or elevated plasma insulin levels. Exposure of muscle and
the liver to elevated levels of free fatty acid combined with signals from
adipocytes could explain the appearance of general insulin resistance. It is
proposed that adipocytes stuffing could be responsible for the appearance of
adipocyte insulin resistance and increased plasma free fatty acids.
Insulin promotes differentiation
of preadipocytes to adipocytes, stimulation of glucose transport in adipocytes,
and synthesis and retention of triglyceride in mature adipocytes. The presence
of normal or elevated plasma free fatty acid (FFA) in the presence of fasting
hyperinsulinemia is taken as clear evidence of insulin resistance of adipose
tissue in obesity and type 2 diabetes.1-5
found commonly in the western diet stimulate glucose transport by a mechanism
that involves translocation and activation of the same glucose transporters as
those used by insulin.6 Enhanced glucose transport due to the
specific effect of fatty acids would increase triglyceride formation in
adipocytes.7 Adipocytes in culture exposed to fatty acids within the
range of the normal physiologic fasting serum fatty acid concentration
displayed increased glucose transport after short-term treatment, and reduced glucose
transporters and impaired insulin stimulated transporter activity after
prolonged exposure.8,9 This observation is taken as evidence for the
existence of a defect in insulin- resistant adipocytes.
intracellular pathways after insulin signaling is suggested to be responsible
for adipocyte insulin resistance.8-11 However, the molecular
mechanism responsible for insulin resistance in adipocytes of obese individuals
is not understood. In addition, we need information regarding the mechanism for
the release of FFA from adipose tissue of lean individuals, considering that
the severity of insulin resistance is the same in lean and obese subjects with
type 2 diabetes.12,13
suggests that the degree of fullness of fat storage capacity could explain the
presence of resistance of adipocytes to insulin and is responsible for the
inappropriate release of FFA from adipose tissue seen in insulin resistant
Adipocytes hypertrophy during the
initial stages of the development of obesity.14,15 However,
adipocytes do not have an unlimited capacity for expansion.14,15
Reaching a critical fat cell size is thought to be necessary to initiate events
that result in increased fat cell number.16,17 Regional differences
in the fat cell size distribution profile suggest that locally produced growth
factors are involved in the regulation of adipocyte hyperplasia.18
Although there are differences between fat depots in different parts of the
body, enlarged adipocytes, especially those in the 140- to 180-µm diameter size
range, secrete growth factors that induce preadipocyte proliferation.19
The association of large adipocytes with paracrine factors that induce the
proliferation of preadipocytes suggests that adipocytes are sensitive to the
degree of fullness, implying a potential limit to adipocyte storage capacity.
occurs as a consequence of normal cell turnover and from the need for more
storage space during weight gain.20 The need for new fat cells could
occur throughout life. Preadipocytes from infants to adults can be induced to
differentiate to adipocytes.21,22 However, aging is associated with
a decline in cellular replicative capacity in the adipocyte precursor system.23
This suggests a potential limit to the expansion of fat storage capacity as one
ADIPOSE SENSITIVITY TO INSULIN
Adipose sensitivity to insulin,
as measured by its effect on the rate of glucose oxidation, was closely related
to the adipose cell size.24 The larger the adipose cells, the less
insulin sensitive they were. Adipose tissue of obese subjects, with enlarged
cells showed a diminished response to insulin. After weight loss and reduction
in adipose cell size, insulin sensitivity of the adipose tissue of obese
individuals was restored to normal.24 These findings suggest that
the size of the adipocyte is involved in the development of "insulin
resistance." The correlation between the adipocyte cell size and reduced
insulin responsiveness indicates that the amount of lipid within the cell may
influence its metabolic efficiency. Restoration of insulin sensitivity of the
adipose tissue of obese individuals after weight loss and reduction in adipose
cell size24 is consistent with this possibility.
Dissolved glucose is always present
in the extracellular fluid and is readily available to all cells.
Except in very few select sites, such as renal proximal tubules, one
or more members of the closely related GLUT family of glucose transporters
mediate glucose transport. The pattern of expression of the GLUT transporters
in different tissues is related to the role of glucose metabolism
in different tissues. Aerobic exercise training is shown to be associated
with an increase in GLUT transporters in the skeletal muscle of young
healthy humans,25 previously sedentary middle aged men,26
individuals with impaired glucose tolerance,27 and individuals
with type 2 diabetes.28 This suggests that utilization
of glucose determines transport of glucose.
translocation of glucose transporters from intracellular storage sites to the
plasma membrane.29,30 In insulin-resistant individuals, it is found
that enlarging adipocytes with a normal capacity for glucose transporter
synthesis have reduced number of recruitable glucose transporters.12,31
This and the diminished insulin-stimulated translocation of glucose
transporters seen in adipocytes of obese individuals and of type 2 diabetics31,32
are consistent with the possibility of an adaptive mechanism based on reduced
need for intracellular glucose. The observed impairment of a glucose transport
mechanism after prolonged exposure of adipocytes in culture to fatty acids8,9
supports this possibility.
plays a minor role compared with skeletal muscle in whole body glucose
disposal. However, "stuffing" the adipocyte with triglyceride may
interfere with its storage functions. Insulin stimulates the synthesis of
intravascular lipase, which liberates fatty acids from triglyceride for uptake
into fat cells. Inside the fat cell, fatty acids are incorporated into
triglyceride by esterification with glycerolphosphate formed from glucose,
which is transported into the cell under the influence of insulin. Inability of
adipocytes to accommodate more triglyceride would allow entry of FFA released
by intravascular lipase into the circulation. Thus, unlike Randle's theory of
resistance of intracellular lipase to insulin,33 limited capacity to
store triglyceride could explain the inappropriate release of FFA from adipose
tissue seen in insulin-resistant states.
The primary basis for the
diagnosis of general insulin resistance is the differences in an individual's
response to insulin-mediated glucose uptake by peripheral (muscle) tissues. The
association of obesity and type 2 diabetes is the major basis for the link
between obesity and insulin resistance. Although all the mechanisms by which
obesity causes systemic insulin resistance remain unknown, obesity is positively
correlated with plasma FFA concentration.34 Increase in FFA
concentration is shown to be associated with decreased insulin-stimulated
glucose uptake.35,36 Accumulation of Acetyl CO-A and other
intermediate products of FFA oxidation could interfere with glucose oxidation
in muscle.33,37-40 In addition, increased plasma FFA could stimulate
hepatic gluconeogenesis41 and increase insulin secretion.42
A high degree of correlation exists between concentrations of plasma glucose
and that of FFA in individuals with type 2 diabetes.1 In short,
elevated FFA levels are thought to be responsible for a significant portion of
general insulin resistance seen in obesity and type 2 diabetes.43
of insulin resistance in peripheral tissues could be mediated by an
adipocyte-secreted signaling molecule called resistin, the blockage of which
improves blood sugar and insulin action.44 Resistin has been found
to modulate insulin-stimulated glucose transport in cultured adipocytes.
Blockage of resistin potentiates insulin-stimulated glucose uptake, and
exposure of adipocytes to resistin reduces insulin-stimulated glucose uptake.44
Taken independently, these data suggest that resistin could be the signal that
links obesity to general as well as adipocyte insulin resistance. However,
taken together, it stands to reason that if adipocytes secrete a signaling
molecule to induce increased peripheral usage of FFA, there could be a
corresponding signal to reduce storage of the same fuel. This is consistent
with the role of adipocytes as a source of a variety of polypeptides that may
affect the action of insulin in other tissues. For example, leptin, secreted by
adipocytes, is involved with the regulation of adipose tissue mass.45
adiposity could be an important factor in the genesis of insulin resistance.
Exposure of the liver to elevated FFA levels coming from intra-abdominal fat
stores could cause reduced clearance of insulin, resulting in hyperinsulinemia.46,47
Although some have not been able to verify this,48-50 the hypothesis
presented is consistent with this possibility. It is possible that the primary
defect in insulin-resistant states is the inability to match the rate of
recruitment of preadipocytes, especially in the location of visceral fat
depots, to the rate of conversion of energy-containing nutrients to fat.
The (PPAR) family of nuclear receptors
represents one of the central regulators of the expression of the
main genes controlling adipocyte differentiation.51-53
adipocyte-specific isoform) expression is increased in omental fat
in obese subjects compared to that seen in omental fat in lean and
moderately overweight subjects.54 This is thought to be
related to the expansion of visceral adipose mass observed in obese
PPARg can be activated by agents of
the thiazolidinedione family. Thiazolidinediones induce conversion of
fibroblast cells into triglyceride-storing adipocytes.55,56 In
clinical studies, thiazolidinediones are found to promote conversion of
preadipocytes to adipocytes in subcutaneous but not in visceral, adipose
tissue.57-59 An explanation for this site-specific effect on
differentiation of human preadipocytes by thiazolidinediones is not available.
However, this is consistent with a reduced availability of
thiazolidinedione-sensitive preadipocytes in visceral fat locations, perhaps
due to prior recruitment during weight gain.
on thiazolidinediones lasting a relatively short term (3 to 4 months) show
improved insulin sensitivity in subjects with type 2 diabetes without
associated weight gain.59,60 However, long-term (6 to 12 months)
clinical studies with thiazolidinediones have resulted in significant weight
gain.57,61-63 This suggests that a significant number of persons
treated with these drugs actually gain weight while improving HbA1c levels. It
is possible that increased insulin sensitivity seen after the administration of
thiazolidinedione is secondary to greater conversion of preadipocytes to fat
cells, greater storage of more triglycerides and resulting decrease in the rate
of fatty acid release, and redistribution away from visceral adiposity. The
finding that non-thiazolidinedione PPARg agonists also show an anti-hyperglycemic
effect along with weight gain64 is consistent with this
of thiazolidinedione has been imagined to increase insulin sensitivity
of muscle and liver, either directly through the low levels of PPARg expressed
in these tissues or indirectly through (TNFa) produced in fat. However,
it is not clear how large an increase in insulin sensitivity these
OBESITY AND TYPE 2 DIABETES
Fifteen percent to 20% of
individuals who develop insulin resistance are nonobese. There is no evidence
to suggest that the mechanism of insulin resistance of adipocyte is different
in nonobese subjects with type 2 diabetes compared with that in obese subjects.
Yet, there is no information regarding the mechanism for the release of FFA
from adipose tissue of lean individuals with type 2 diabetes. The finding that
the severity of insulin resistance is the same in lean and obese diabetic
subjects12,13 is consistent with the possibility of adipocyte storage
capacity being more important than body fatness in the genesis of insulin
resistance. Based on the hypothesis presented, lean individuals could develop
elevated FFA levels after gaining weight considered acceptable according to
weight tables because of reduced capacity to store triglyceride compared with
obese individuals. Improved insulin sensitivity seen following increased
adipogenesis after treatment with thiazolidinediones in nonobese individuals57
supports this position.
strongly correlated with insulin resistance as evidenced by significant
increase in glucose transport, reduction in free fatty acid levels, and
decrease in plasma insulin level seen after weight loss.65,66
However, many individuals will not develop insulin resistance despite profound
obesity. A very large capacity to accommodate additions in fat mass could
explain this finding. Adipocyte size and number are greater in obese than in
lean individuals.67,68 The ability to match fat cell acquisition
with fat accumulation could explain normoglycemia in the presence of
hyperinsulinemia seen in some obese individuals who do not develop insulin
resistance.69 At the other end of the spectrum could be the entity
called lipoatrophy characterized by complete absence of subcutaneous fat
tissue. Although the factors responsible for the decrease in fat tissue are
unknown, this condition is associated with hyperglycemia, hypertriglyceridemia,
and elevated FFA in the presence of normal or elevated serum insulin levels.70
presented is not at odds with the finding that fat accumulation in muscle could
contribute to insulin resistance at that site.71 Nor is it in
opposition to the prevailing understanding of the role of impaired islet cell
secretion in the etiology of hyperglycemia of type 2 diabetes.
Muscles are capable of using large
amounts of fatty acids for energy. Use of this capacity could result in
decreased utilization of glucose. The switch to FFA for energy could spare
large amounts of glucose since carbohydrates are usually used preferentially by
muscles. High levels of FFA and endocrine signals from adipocytes could be
responsible for the apparent defect in glucose transport and utilization. It is
proposed that adipocyte stuffing could be responsible for the appearance of
adipocyte insulin resistance and increased plasma FFA.
The author thanks Antony M.
Poothullil, MD, for carefully reading the manuscript and for helpful
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