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Division of Biological Sciences and Department of Nutrition (K.T.U., L.S., S.M.W., G.S.H.), Harvard School of Public Health, Boston, Massachusetts 02115; and Research Division (S.B.W.), Joslin Diabetes Center, Boston, Massachusetts 02215
Address all correspondence and requests for reprints to: Gökhan S. Hotamisligil, M.D., Ph.D., Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115. E-mail: ghotamis{at}hsph.harvard.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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25 kg/m2) in the United
States population (1, 2), is a major risk factor for the development of
type 2 diabetes and associated pathological states such as
dyslipidemia, hypertension and atherosclerosis (3, 4). More than 80%
of individuals with type 2 diabetes are obese (5). The pathogenesis of
type 2 diabetes involves the progressive development of
hyperinsulinemia and insulin resistance, a decreased response to
insulin in target tissues (6). Another hallmark of the disease is
impaired ß-cell function that, at least in some cases, is already
detectable in stages preceding overt hyperglycemia (7). Although the
principal defects of type 2 diabetes are clear, how an expanded fat
mass results in any of these pathologies is not well understood. Possible factors for obesity-induced disorders are lipid molecules that are elevated in obesity, such as long chain nonesterified fatty acids (FFA; FFA). In agreement with a role of systemic FFA in the development of type 2 diabetes, it has been shown that elevation of plasma FFA induces peripheral insulin resistance in humans and rodent models within few hours (8, 9, 10). In addition, it has been shown that FFA can have positive or negative effects on insulin secretion, depending on the experimental conditions (11, 12, 13, 14, 15, 16, 17, 18). Thus, obesity-induced elevation of systemic FFA might have direct impact on glucose homeostasis via systemic insulin sensitivity and possibly through effects on insulin secretion.
Adipocyte fatty acid-binding protein, aP2, is a member of the intracellular fatty acid binding protein family (19) highly expressed in adipocytes (20, 21). While the exact cellular functions of aP2 remain largely undefined, our earlier work has indicated an important in vivo role for this protein in lipid and glucose metabolism. Mice deficient for aP2 (aP2-/-) were shown to be protected from development of insulin resistance and hyperinsulinemia in a high fat diet-induced obesity model, establishing aP2-/- mice as an experimental system to study the pathogenesis of type 2 diabetes (22). In subsequent studies with lean animals, it was shown that the lipolytic response was attenuated in aP2-/- mice and isolated aP2-/- adipocytes (23, 24). Furthermore, lipolysis- associated insulin secretion in the lean aP2-/- mice was profoundly reduced although the pancreatic response to other insulin secretagogues was unaltered (23). Although the mechanisms underlying these changes are not yet clear, the interesting possibility was raised that an intrinsically reduced propensity to secrete insulin in response to lipid or other meditors might contribute to the protection of aP2-/- mice from hyperinsulinemia and consequently insulin resistance.
To test the relevance of these observations in obesity, in a uniform genetic setting, we generated ob/ob mice lacking aP2. In these animals, parameters relevant to obesity, insulin resistance, insulin secretion, and plasma lipids were studied longitudinally to assess the overall effect of aP2-deficiency on obesity-related metabolic abnormalities. Lipolysis, lipolysis-associated insulin secretion, and ß cell function were studied in more detail in a subset of animals. Our results demonstrate that aP2-deficiency has significant beneficial effects on insulin resistance in the ob/ob model, and that the lack of aP2 results in reduced lipolysis and lipolysis-induced insulin secretion in obesity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Metabolic measurements
Total body weights were measured monthly from age 4–16 weeks.
Blood samples were collected at 4, 8, and 12 weeks of age. Glucose
concentrations in plasma were measured using glucose analyzer glucose
strips (Medisense, Bedford, MA). Serum insulin and
C-peptide were measured with a monoclonal insulin RIA (Linco Research, Inc., St. Louis, MO). Glucose and insulin tolerance
tests were performed on conscious male animals following a 24 h
fast by ip administration of glucose (1.8 mg/g) and measurements of
tail blood glucose at 15, 30, 45, 60, 90, and 120 min. The insulin
tolerance test was done similarly except for the injection of
recombinant mouse insulin (1 U/kg, Sigma, St. Louis, MO)
and an additional blood glucose measurement at 150 min. Plasma
tri-glycerides, glycerol, cholesterol, and FFA levels were measured
using commercially available color enzymatic assays (Sigma
and Wako Pure Chemical Industries Ltd., Richmond,
VA). In both CL 316,243- (ß3-adrenoreceptor specific agonist
provided by Dr. K. Steiner, Wyeth-Ayerst Laboratories, Inc., Princeton, NJ) stimulated lipolysis and glucose-stimulated
insulin secretion experiments, the animals were fasted 24 h before
the experiments. The compounds were dissolved in PBS and injected ip at
a dose of 0.1 mg/kg (CL 316,243) and 1.8 mg/g (glucose). In all
experiments, except the tolerance tests, blood was collected from the
orbital plexus after anesthetizing animals with methoxyflurane
(Mallinckrodt, Inc. Veterinary). Dynamic experiments were
performed in males, whereas steady-state measurements were in both
males and females. For all measurements, such as tolerance tests, CL
316,243 stimulated lipolysis, or glucose-stimulated insulin secretion,
statistical analysis was performed using ANOVA repeated
measurements.
Staining of pancreatic sections
Following administration of an overdose of sodium amytal,
pancreas was excised from each animal in toto. After
excision, each pancreas was lightly blotted, weighed, fixed in Bouin’s
fixative, and embedded in paraffin by routine techniques. Sections were
immunostained (immunoperoxidase) to examine the ß cells using
antibodies against insulin (guinea pig antiporcine insulin, Linco Research, Inc., St. Charles, MO, 1:200) or the non-ß-endocrine
cells of the islet (the mantle) using a cocktail of antibodies against
glucagon (antibovine final dilution 1:3000, gift of Dr. M. Appel),
somatostatin (rabbit antisynthetic final dilution 1:300, made in the
laboratory of Dr. S. Bonner-Weir), and pancreatic polypeptide (rabbit
antibovine final dilution 1:3000, gift of Dr. R. Chance, Eli Lilly & Co., Indianapolis, IN). The sections were incubated
overnight at 4 C, washed in PBS, incubated with goat antirabbit IgG as
a secondary antibody, washed with Tris buffer (pH 7.4), incubated with
a peroxidase antirabbit serum (Cappel Laboratories, Cochranville, PA),
stained with 3,3'-diaminobenzidine tetrahydrochloride
(Sigma Immunochemicals) and counterstained with
hematoxylin. Insulin staining was done similarly except for the use of
a goat anti guinea pig secondary antibody. The slides were evaluated
blindly to the genotype of the animals.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, no significant difference in body
weight was observed between lean aP2-deficient and wild-type animals.
However, throughout the study period, ob/ob mice deficient in aP2
(ob/ob-aP2-/-) displayed
increased obesity compared with obese control animals (ob/ob). At 16
weeks of age both male and female
ob/ob-aP2-/- mice weighed
15% more compared with ob/ob animals (P < 0.001).
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). No significant difference in fat pad weight was
observed between lean
aP2-/- and
aP2+/+ animals in both sexes. However, the fat
pad weights of
ob/ob-aP2-/- mice of both
sexes were significantly higher compared with ob/ob controls,
suggesting increased adiposity in these animals (3.4 ± 0.08
vs. 2.4 ± 0.08 g in males and 4.9 ± 0.12
vs. 4.0 ± 0.08 g in females, P <
0.001).
Glucose homeostasis
To determine the effects of the absence of aP2 on glucose
metabolism, we measured glucose and insulin levels in both steady
(after 6-h day time food withdrawal) and fasted (24 h) states. The lean
animals remained euglycemic throughout the study, and there was no
significant difference in blood glucose between lean
aP2-/- and
aP2+/+ mice in either condition (Table 1). Similarly, the plasma insulin levels
of all lean mice were within normal boundaries in the fed state. In the
fasted state, insulin levels of male
aP2-/- mice were higher
than that of the aP2+/+ animals, but this
difference did not reach statistical significance in the females. In
all obese groups, the animals developed hyperglycemia and
hyperinsulinemia compared with the lean controls. However, both
conditions were significantly improved in the
aP2-/- animals and in
both sexes, ob/ob-aP2-/-
displayed lower plasma glucose and insulin levels, indicating a better
glucose homeostasis. Overall, plasma glucose levels in
ob/ob-aP2-/- mice were
decreased by 20–25% in both sexes compared with ob/ob controls
(P < 0.001). Similarly, a 35–40% reduction in plasma
insulin levels was evident in
ob/ob-aP2-/- in both
conditions and in both sexes.
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). The deficiency of aP2 had no effect
on insulin sensitivity in the lean groups. However, in obese animals,
the ob/ob-aP2-/- mice
displayed a significantly stronger hypoglycemic response to a given
dose of insulin compared with ob/ob controls, which is consistent with
increased insulin sensitivity. Similarly, following the administration
of glucose, ob/ob-aP2-/-
animals displayed improved glucose profiles consistent with increased
insulin sensitivity compared with the ob/ob animals (Fig. 2).
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). However, female
ob/ob-aP2-/- mice had
lower plasma cholesterol levels compared with ob/ob controls (10–15%
decrease, P < 0.01). This difference was only 5% in
males and was not statistically significant. aP2 deficiency also had
moderate effects in reducing plasma triglyceride levels, under some but
not all conditions. In the lean group, plasma triglyceride levels were
decreased 15% in males and 26% in females (P <
0.001) in fasted animals but no significant difference was observed in
the steady-state (Table 1). In contrast,
ob/ob-aP2-/- mice of both
sexes had significantly lower steady state plasma triglyceride levels
(25% in males and 10% in females, P < 0.01) compared
with ob/ob controls.
Plasma glycerol and FFA
Increased FFAs are associated with obesity and have been
postulated to be causally involved in the development of
hyperinsulinemia and insulin resistance (10, 25, 26). To test if
systemic FFA levels play a role in the observed improvement in insulin
sensitivity in
ob/ob-aP2-/- mice, we
measured plasma levels of FFA and glycerol, the two products of
lipolysis, under both basal and CL 316,243-stimulated conditions.
Baseline plasma glycerol levels were lower in
aP2-/- lean and obese
animals of both sexes (Table 1). This decrease was 12–18% in the lean
and 15% in the obese groups (P < 0.04). In the fasted
state the glycerol levels increased in all mice and no difference was
evident between aP2-/-
and aP2+/+ animals. In general, a small (10%,
P < 0.05), but consistent increase was observed in the
plasma FFA levels of
aP2-/- mice with the
exception of lean animals in the steady-state (Table 1). In the obese
group, the aP2-deficient mice also had higher plasma FFA levels
(14–20% in the steady state and 26–29% after fasting,
P < 0.01).
Lipolysis
Lipolysis is an adipocyte function that might contribute to the
development of insulin resistance in obesity (27, 28). Thus, we
examined in vivo lipolysis stimulated by CL-316,243 (0.1
mg/kg), a specific agonist of the ß3-adrenergic receptor (ß3-AR)
(29), which is primarily expressed in adipose tissue and
gastrointestinal tract (30, 31). For these experiments, blood samples
were collected before and 8, 16, 30 and 60 min after the ip injection
of 0.1 mg/kg CL 316,243. While plasma glycerol levels increased over
basal levels in all animals, the extent of this increase was
significantly smaller in both lean and obese aP2-deficient mice (Fig. 3A). At 8 min, when the response is
maximal, the rise in plasma glycerol levels was 2.2-fold in
ob/ob-aP2-/- mice
compared with the 2.8-fold increase in
ob/ob-aP2+/+ controls (P <
0.05). Similar to glycerol, FFA levels also increased in all animals
following CL 316,243 administration reaching maximum levels at 30 min
(Fig. 3B). This increase, however, was much smaller in both lean and
obese aP2-deficient animals throughout the experiment. At 30 min, the
plasma FFA levels of
ob/ob-aP2-/- animals
increased by only 1.8-fold, whereas a 2.8-fold increase was evident in
ob/ob controls indicating a reduced lipolytic response associated with
aP2-deficiency.
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). In the lean group, the plasma
insulin levels started to increase by 8 min and reached a maximum at 30
min. At this time, the plasma insulin levels were increased by 24- and
52-fold in aP2-/- and
aP2+/+ mice, respectively. This difference
between the lean groups subsided by 60 min. In the obese groups, a
notable rise in circulating insulin levels was not detected until 30
min after stimulation. The increase in plasma insulin levels in the
ob/ob-aP2-/- (2- and
4-fold) was significantly smaller than ob/ob controls (4- and 6-fold)
at 30 and 60 min, respectively. These data demonstrate that the insulin
secretory response to lipolytic stimulation is strikingly reduced in
aP2-deficient animals.
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, B and C). In the
obese group, the overall response to glucose was not robust.
Interestingly, aP2-deficiency rendered ob/ob mice more responsive to
glucose, reflected in higher plasma insulin and C-peptide
concentrations following glucose administration compared with control
animals. One hour after glucose injection, plasma insulin levels of
ob/ob-aP2-/- mice was
increased by 2.5-fold, whereas there was almost no change in plasma
insulin levels of the ob/ob mice. Similarly, C-peptide levels increased
2-fold in ob/ob-aP2-/-
mice, whereas no response to glucose was evident in the ob/ob
animals.
Finally, to determine whether any of the observed differences in
insulin secretion were due to differences in pancreatic islet size or
composition, we examined the pancreas of lean and obese aP2-deficient
animals by immunohistochemistry. Islet morphology (size, shape, and
organization of the non-ß-cell mantle) was evaluated in blind
fashion. Genotypes could not be separated on the basis of differences
in pancreatic morphology. There was no significant difference in the
pancreatic morphology or weight between wild-type and aP2-deficient
mice (Fig. 5). No significant differences were also evident in the
extent of islet degranulation in
aP2-/- and
aP2+/+ obese animals compared with their lean
counterparts. In addition, the obese animals, regardless of their
genotype, had similar amounts of fat droplets scattered between the
lobes and in the exocrine portion of pancreas (see Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Much attention has been placed on muscle tissue in systemic insulin resistance, both due to its mass and the fact that defective insulin action is detectable at this site early in the development of type 2 diabetes. Interestingly, recent studies with genetic rodent models have put unexpected weight on the role of adipose tissue and pancreatic islets as dominant sites impacting systemic insulin resistance and development of type 2 diabetes (34, 35, 36, 37, 38, 39). In line with this notion are findings in mice genetically deficient in aP2, the adipocyte fatty acid-binding protein. The expression of aP2 is highly restricted to differentiated adipocytes (20, 21) and recently it has been detected in activated macrophages ( Ref. 40 and our unpublished results). In a dietary model of obesity, aP2-deficiency leads to substantially increased insulin sensitivity (22), demonstrating that an isolated defect in the lipid biology of adipocytes might have a significant systemic effect on the course of obesity-induced hyperinsulinemia and insulin resistance.
How could an alteration in adipose lipid metabolism effect systemic glucose metabolism? A potential scenario is that expansion of fat tissue and concomitant insulin resistance of adipocytes will lead to increased lipolysis and release of byproducts such as FFA and cytokines from adipose tissue, eventually resulting in reduced glucose disposal and increased hepatic glucose production. This then stimulates the secretion of insulin to compensate for insulin resistance. Hyperinsulinemia further promotes insulin resistance at target sites through receptor desensitization and, indirectly, through its effects on lipogenesis. This vicious cycle will eventually result in chronic hyperglycemia, defective glucose-stimulated insulin secretion, ß-cell pathologies and development of frank diabetes. According to this model, one potential strategy to disturb this vicious cycle will be to enhance insulin action in adipose tissue and prevent excess adipose tissue lipolysis. If the output of the adipose tissue is a critical and early stimulus for hyperinsulinemia in obesity, then decreased lipolysis and the associated products should be associated with lower rates of insulin secretion, and preservation of the ß cell response to glucose.
Interestingly, in studies using lean animals, our group as well as Coe et al., have recently demonstrated decreased lipolysis in aP2-/- adipocytes in vitro and aP2-/- mice in vivo (23, 24). The molecular mechanisms underlying impaired lipolysis in the absence of aP2 are not yet clear. In adipose tissue of aP2-deficient mice, there does not appear to be any quantitative defect in the major components of the lipolytic machinery. Interestingly, recent studies demonstrated that aP2 directly interacts with hormone sensitive lipase (HSL), raising the possibility that this interaction is critical in the efficiency of this enzyme (41).
During studies on lipolysis, we also made the intriguing observation that lipolysis-associated insulin secretion was dramatically reduced in lean aP2-/- mice while the response to other insulin secretagogues remained intact (23). These observations prompted us to postulate that the decreased lipolysis and the subsequent insulin secretory response to the lipolytic products of the adipocyte might underlie the improved overall glucose homeostasis in obese aP2-/- animals. To directly test this hypothesis, we have generated genetically obese mice by intercrossing aP2-/- animals with the ob/ob mice, to establish a well-defined obesity model with aP2-deficiency.
In support of earlier observations in diet-induced obesity, this study clearly demonstrated that aP2-deficiency is associated with significantly improved glucose and lipid metabolism even in the presence of extreme obesity resulting from leptin deficiency. Although ob/ob-aP2-/- mice were even heavier than the ob/ob-aP2+/+ animals, they displayed a much improved glucose metabolism compared with the obese controls. This was manifested in significantly lower plasma glucose and insulin levels throughout the experimental period and by their better performance in insulin and glucose tolerance tests. The insulin-sensitizing effect of aP2-deficiency was limited to the obese state, as we did not observe a trend toward higher insulin sensitivity in lean aP2-/- animals. These improvements were, however, not complete since the ob/ob-aP2-/- mice still displayed insulin resistance compared with lean animals.
Next, we tested whether aP2-deficiency leads to alterations in lipolysis and ß cell responses in the presence of severe obesity. First, we demonstrated that the lipolytic response to ß3-adrenergic receptor stimulation is significantly decreased in lean and, even more so, in the obese aP2-/- mice compared with control animals. This was shown by a reduction in the levels of both glycerol and FFA levels upon ß3-AR stimulation in aP2-/- and ob/ob aP2-/- mice. In our previous studies, we have observed significant alterations in glycerol but not in FFA levels in lean animals upon lipolytic stimuli. The extent of this response appears to be related to the metabolic state of the animals because, as shown here, 24 h fasting led to decreased responses in both glycerol and FFA, whereas our previous experiments, performed in the day time resting state, led only to decreased glycerol response (23).
Second, we demonstrate that in both lean and obese mice the lipolysis-associated increase in plasma insulin was substantially reduced in aP2-/- animals compared with their respective controls following ß3-adrenergic stimulation. Similar results were also observed in aP2-/- mice made obese by a high fat diet (data not shown). These alterations were not related to a pancreatic defect or general unresponsiveness of the islets. No significant alterations were evident in the morphology of the pancreatic ß cells between aP2-/- and aP2+/+ animals. The glucose-stimulated insulin secretion was normal and comparable to the lean mice. Most strikingly, glucose-stimulated insulin secretion was partially preserved in ob/ob aP2-/- mice, whereas it was completely abolished in ob/ob controls. These data are consistent with the increased glucose tolerance in these animals and show that the beneficial effect of aP2 deficiency is not only manifested in enhanced peripheral insulin sensitivity but also in better maintained pancreatic ß cell function, both of which potentially contribute to improved glucose metabolism.
The mechanisms by which aP2-deficiency leads to improved metabolic
control in obesity are not known. Our studies in the dietary obesity
model have suggested that lack of obesity-induced TNF
production in
adipose tissue might be part of this improved response (22). However,
in the more severe obesity model, our preliminary studies did not
demonstrate a significant reduction in TNF expression in
ob/ob-aP2-/- animals
suggesting that there are additional pathways modified by the absence
of aP2 leading to improved insulin sensitivity (data not shown).
Because aP2 binds to cytosolic fatty acids and could modulate their
intracellular concentrations, availability or subcellular trafficking,
we have also postulated that in the absence of this fatty acid binding
activity, the activity of nuclear hormone receptors that are regulated
by fatty acid ligands could be altered. Because the PPAR family of
nuclear hormone receptors play a dramatic role in glucose and lipid
metabolism, they will be the prime candidates for further examination.
Although our preliminary analysis have not yet yielded support for this
hypothesis, further studies will be necessary to definitively address
this possibility.
In any case, data presented here further support the concept of an adipopancreatic axis, the function of which is specifically altered in the absence of adipocyte aP2. How aP2-deficiency leads to reduction in lipolysis-associated insulin secretion and provides some protection from deterioration of glucose-stimulated insulin secretion in the context of obesity remains to be shown. For the development of the latter pathological state, chronic elevation of systemic FFA has been proposed as a causal signal (14). In this study, we have seen a small but consistent increase in basal plasma FFA levels in both lean and obese aP2-/- mice, which argues against a potential role for these molecules. On the other hand, lipolytic response is reduced, and the temporal and spatial dynamics of FFA output might still be altered and play a critical role for this physiological state. It is also possible that although small in magnitude, the elevation in basal FFA levels is sufficient to insensitize the islets to further lipid-derived stimuli. In any case, it is clear that the phenotype of the aP2-/- mice makes these animals a suitable model to study the interaction between adipocytes and the islets and qualifies aP2 as a very interesting drug target for the treatment of insulin resistance, dyslipidemia, and diabetes.
Received March 13, 2000.
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References |
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activation induces the expression of the adipocyte fatty acid
binding protein gene in human monocytes. Biochem Biophys Res Commun 261:456–458[CrossRef][Medline]
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 P. Dandona, A. Aljada, A. Chaudhuri, and A. Bandyopadhyay The Potential Influence of Inflammation and Insulin Resistance on the Pathogenesis and Treatment of Atherosclerosis-Related Complications in Type 2 Diabetes J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2422 - 2429. [Full Text] [PDF]
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K. Maeda, K. T. Uysal, L. Makowski, C. Z. Gorgun, G. Atsumi, R. A. Parker, J. Bruning, A. V. Hertzel, D. A. Bernlohr, and G. S. Hotamisligil Role of the Fatty Acid Binding Protein mal1 in Obesity and Insulin Resistance Diabetes, February 1, 2003; 52(2): 300 - 307. [Abstract] [Full Text] [PDF]
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 S. Lucas, G. Tavernier, C. Tiraby, A. Mairal, and D. Langin Expression of human hormone-sensitive lipase in white adipose tissue of transgenic mice increases lipase activity but does not enhance in vitro lipolysis J. Lipid Res., January 1, 2003; 44(1): 154 - 163. [Abstract] [Full Text] [PDF]
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A. V. Hertzel, A. Bennaars-Eiden, and D. A. Bernlohr Increased lipolysis in transgenic animals overexpressing the epithelial fatty acid binding protein in adipose cells J. Lipid Res., December 1, 2002; 43(12): 2105 - 2111. [Abstract] |
