Abstract
White adipose tissue has distinctive angiogenic properties. White adipocytes are capable of producing vascular endothelial growth factor (VEGF) in response to insulin and catecholamines. Recognizing the dual functions of adipose tissue as an endocrine/metabolic organ and fuel storage depot with an inimitable ability to adjust its organ mass, our aim was to determine whether fasting would affect adipocyte VEGF165 production. Rats were fed ad libitum, then fasted for 24 hours, and then refed after the 24-hour fast. The isolated white adipocytes from each group and blood endocrine/metabolic profiles were examined at each stage, yielding three sets of results. Using cultured adipocytes, fasting caused a two-fold increase in VEGF165 formation compared to fed rats that normalized after refeeding. Likewise, freshly prepared adipocytes manifested a three-fold augmentation in adipocyte VEGF165 mRNA expression and a 60 % increase the transcriptional regulator hypoxia-inducible factor 1 (HIF-1α) that normalized after refeeding. Blood studies revealed the expected fasting-related alterations in glucose, β-hydroxybutyrate and corticosterone. Plasma VEGF concentrations were attenuated by 26 % with fasting, and did not normalize with refeeding. Multiple linear regression analyses uncovered statistically significant inverse correlations between plasma VEGF and blood β-hydroxybutyrate or serum corticosterone. Blood glucose, in contrast, correlated directly with plasma VEGF. We will discuss the potential role of enhanced adipocyte VEGF formation during starvation in light of the known actions of this factor on vascular endothelial mitogenesis and permeability.
Key words
Fasting - Adipose tissue - Vascular permeability - Hypoxia-inducible factor 1
References
-
1
Castellot J, Karnovsky M, Spiegleman B.
Potent stimulation of vascular endothelial cell growth by differentiated 3T3L1 cells.
Proc Natl Acad Sci.
1980;
77
6007-6011
-
2
Silverman K. et al .
Angiogenic activity of adipose tissue.
Biochem Biophys Res Comm.
1988;
153
347-352
-
3
Mandrup S. et al .
Inhibition of 3T3-L1 adipocyte differentiation by expression of acyl-CoA-binding protein antisense RNA.
J Biol Chem.
1998;
273 (37)
23 897-23 903
-
4
Claffey K P, Wilkison W O, Spiegelman B M.
Vascular endothelial growth factor: regulation by cell differentiation and activated second messenger pathways.
J Biol Chem.
1992;
23
16 317-16 322
-
5
Zhang Q X. et al .
Vascular endothelial growth factor is the major angiogenic factor in omentum: mechanism of the omentum-mediated angiogenesis.
J Surg Res.
1997;
67
147-154
-
6
Asano A. et al .
Adrenergic activation of vascular endothelial growth factor mRNA expression in rat brown adipose tissue: implication in cold-induced thermogenesis.
Biochem J.
1997;
328
179-183
-
7
Hausman G J, Richardson R L.
Cellular and vascular development in immature rat adipose tissue.
J Lipid Res.
1983;
24
522-532
-
8
Crandall D, Hausman G, Kral J.
A review of the microcirculation of adipose tissue: anatomic, metabolic and angiogenic perspectives.
Microcirculation.
1997;
4
211-230
-
9
Crandall D L, DiGirolamo M.
Hemodynamic and metabolic correlates in adipose tissue: pathophysiologic considerations.
FASEB J.
1990;
4
141-147
-
10
Ferrara N, Davis-Smyth T.
The biology of vascular endothelial growth factor.
Endocrine Reviews.
1997;
18
4-25
-
11
Yang R. et al .
Effects of vascular endothelial growth factor on hemodynamics and cardiac performance.
J Cardiovasc Pharmacol.
1996;
27
838-844
-
12
Zachary I.
Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor.
Am J Physiol Cell Physiol.
2001;
280
C1375-C1386
-
13
Mick G, Wang X, McCormick K L.
White adipocyte vascular endothelial growth factor (VEGF): regulation by insulin.
Endocrinology.
2002;
143
948-953
-
14
Roche E. et al .
Palmitate and oleate induce the immediate-early response genes c-fos and nur-77 in the pancreatic beta-cell line INS-1.
Diabetes.
1999;
48 (10)
2007-2014
-
15
de Boer S F. et al .
Effects of fasting on plasma catecholamine, corticosterone and glucose concentrations under basal and stress conditions in individual rats.
Physiol Behav.
1989;
45 (5)
989-994
-
16
de Boer S F, van der Gugten J.
Daily variations in plasma noradrenaline, adrenaline and corticosterone concentrations in rats.
Physiol Behav.
1987;
40 (3)
323-328
-
17
Yancopoulos G D. et al .
Vascular-specific growth factors and blood vessel formation.
Nature.
2000;
407
242-248
-
18
Rosell S, Belfrage E.
Blood circulation in adipose tissue.
Physiological reviews.
1979;
59 (4)
1078-1104
-
19
DiGirolamo M. et al .
Relationship of adipose tissue blood flow to fat cell size and number.
Am J Physiol.
1971;
220
932-937
-
20
Gerber H P. et al .
VEGF is required for growth and survival in neonatal mice.
Development.
1999;
126 (6)
1149-1159
-
21
Cameliet P.
Mechanisms of angiogenesis and arteriogenesis.
Nature Medicine,.
2000;
6
389-395
-
22
Wulff C. et al .
Luteal angiogenesis: Prevention and intervention by treatment with vascular endothelial growth factor TrapA40.
J Clin Endo Metab.
2001;
86
3377-3386
-
23
Rupnick M A. et al .
Adipose tissue mass can be regulated through the vasculature.
Proc Natl Acad Sci USA.
2002;
99 (16)
10 730-10 735
-
24
Engeli S, Sharma A M.
Role of adipose tissue for cardiovascular-renal regulation in health and disease.
Horm Metab Res.
2000;
32 (11 - 12)
485-499
-
25
Hajri T, Abumrad N A.
Fatty acid transport across membranes: relevance to nutrition and metabolic pathology.
Annu Rev Nutr.
2002;
22
383-415
-
26
Bartness T J, Bamshad M.
Innervation of mammalian white adipose tissue: implications for the regulation of total body fat.
Am J Physiol.
1998;
275 (5 Pt 2)
R1399-R1411
-
27
Langin D, Lucas S, Lafontan M.
Millennium fat-cell lipolysis reveals unsuspected novel tracks.
Horm Metab Res.
2000;
32
443-452
-
28
Senger D R. et al .
Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.
Science.
1983;
219
983-985
-
29
Bates D O, Curry F E.
Vascular endothelial growth factor increases hydraulic conductivity of isolated perfused microvessels.
Am J Physiol.
1996;
271 (6 Pt 2)
H2520-H2528
-
30
Bates D O, Lodwick D, Williams B.
Vascular endothelial growth factor and microvascular permeability.
Microcirculation,.
1999;
6 (2)
83-96
-
31
Hippenstiel S. et al .
VEGF induces hyperpermeability by a direct action of endothelial cells.
Am J Physiol.
1998;
274
L678-L684
-
32
LeCouter J, Ferrara N.
EG-VEGF and the concept of tissue-specific angiogenic growth factors.
Semin Cell Dev Biol.
2002;
13 (1)
3-8
-
33
Semenza G.
HIF-1: mediator of physiological and pathophysiological responses to hypoxia.
J Appl Physiol.
2000;
88
1474-1480
-
34
Kvietikova I. et al .
The hypoxia-inducible factor-1 DNA recognition site is cAMP-responsive.
Kidney Int.
1997;
51 (2)
564-566
-
35
Firth J D, Ebert B L, Ratcliffe P J.
Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements.
J Biol Chem.
1995;
270 (36)
21 021-21 027
-
36
Thacker S V, Nickel M, DiGirolamo M.
Effects of food restriction on lactate production from glucose by rat adipocytes.
Am J Physiol.
1987;
253 (4 Pt 1)
E336-E342
-
37
Newby F D. et al .
Adipocyte lactate production remains elevated during refeeding after fasting.
Am J Physiol.
1990;
259 (6 Pt 1)
E865-E871
-
38
Dantz D. et al .
Vascular endothelial growth factor: a novel endocrine defensive response to hypoglycemia.
J Clin Endocrinol Metab.
2002;
87 (2)
835-840
-
39
Brooks S E. et al .
Modulation of VEGF production by pH and glucose in retinal Muller cells.
Curr Eye Res.
1998;
17 (9)
875-882
-
40
Dallman M F. et al .
Starvation: early signals, sensors, and sequelae.
Endocrinology,.
1999;
140 (9)
4015-4023
-
41
Hanson E S, Levin N, Dallman M F.
Elevated corticosterone is not required for the rapid induction of neuropeptide Y gene expression by an overnight fast.
Endocrinology.
1997;
138 (3)
1041-1047
-
42
Tonello C. et al .
Role of sympathetic activity in controlling the expression of vascular endothelial growth factor in brown fat cells of lean and genetically obese rats.
FEBS Lett.
1999;
442 (2 - 3)
167-172
-
43 Vernon R G, Clegg R A. 1985 The metabolism of white adipose tissue in vivo and in vitro. In: New Perspectives in Adipose Tissue: Structure, Function and Development. A. Cryer and R.L.R. Van, eds. London; Butterworth and Co Ltd 65-81
-
44
Brausewetter F. et al .
Microvascular permeability is increased in both types of diabetes and correlates differentially with serum levels of insulin-like growth factor I (IGF-I) and vascular endothelial growth factor (VEGF).
Horm Metab Res.
2001;
33 (12)
713-720
-
45
Miyazawa S. et al .
Increase in serum vascular endothelial growth factor in obese subjects:relationship to body fat distribution.
Diabetes.
2002;
51 (Supplement 2)
A404-A405
-
46
Keyt B A. et al .
The carboxyl-terminal domain (111 - 165) of vascular endothelial growth factor is critical for its mitogenic potency.
J Biol Chem.
1996;
271 (13)
7788-7795
-
47
Iozzo R V, San A ntonio.
Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena.
J Clin Invest.
2001;
108 (3)
349-355
G. Mick
University of Alabama at Birmingham · Dept. of Pediatrics · Endocrinology
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