TY - JOUR
T1 - A unique mechanism of desensitization to lipolysis mediated by β3- adrenoceptor in rats with thermal injury
AU - Ikezu, Tsuneya
AU - Yasuhara, Shingo
AU - Granneman, James G.
AU - Kraemer, Fredric B.
AU - Okamoto, Takashi
AU - Tompkins, Ronald G.
AU - Martyn, Jeevendra A.J.
PY - 1999/8
Y1 - 1999/8
N2 - Thermal injury causes a hypermetabolic state associated with increased levels of catabolic hormones, but the molecular bases for the metabolic abnormalities are poorly understood. We investigated the lipolytic responses after β3-adrenoceptor (β3-AR) agonists and evaluated the associated changes in β-AR and its downstream signaling molecules in adipocytes isolated from rats with thermal injury. Maximal lipolytic responses to a specific β3-AR agonist, BRL-37344, were significantly attenuated at post burn days (PBD) 3 and 7. Despite significant reduction of the cell surface β3-AR number and its mRNA at PBD 3 and 7, BRL-37344 and forskolin- stimulated cAMP levels were not decreased. Glycerol production in response to dibutyryl cAMP, a direct stimulant of hormone-sensitive lipase (HSL) via protein kinase A (PKA), was significantly attenuated. Although immunoblot analysis indicated no differences in the expression and activity of PKA or in the expression of HSL, HSL activity showed significant reductions. Finally, β3-AR-induced insulin secretion was indeed attenuated in vivo. These studies indicate that the β3-AR system is desensitized after burns, both in the adipocytes and in β3-AR-induced secretion of insulin. Furthermore, these data suggest a complex and unique mechanism underlying the altered signaling of lipolysis at the level of HSL in animals after burns.
AB - Thermal injury causes a hypermetabolic state associated with increased levels of catabolic hormones, but the molecular bases for the metabolic abnormalities are poorly understood. We investigated the lipolytic responses after β3-adrenoceptor (β3-AR) agonists and evaluated the associated changes in β-AR and its downstream signaling molecules in adipocytes isolated from rats with thermal injury. Maximal lipolytic responses to a specific β3-AR agonist, BRL-37344, were significantly attenuated at post burn days (PBD) 3 and 7. Despite significant reduction of the cell surface β3-AR number and its mRNA at PBD 3 and 7, BRL-37344 and forskolin- stimulated cAMP levels were not decreased. Glycerol production in response to dibutyryl cAMP, a direct stimulant of hormone-sensitive lipase (HSL) via protein kinase A (PKA), was significantly attenuated. Although immunoblot analysis indicated no differences in the expression and activity of PKA or in the expression of HSL, HSL activity showed significant reductions. Finally, β3-AR-induced insulin secretion was indeed attenuated in vivo. These studies indicate that the β3-AR system is desensitized after burns, both in the adipocytes and in β3-AR-induced secretion of insulin. Furthermore, these data suggest a complex and unique mechanism underlying the altered signaling of lipolysis at the level of HSL in animals after burns.
KW - Adrenergic receptor
KW - Burns
KW - Hormone-sensitive lipase
KW - Insulin
KW - Protein kinase A
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U2 - 10.1152/ajpendo.1999.277.2.e316
DO - 10.1152/ajpendo.1999.277.2.e316
M3 - Article
C2 - 10444428
AN - SCOPUS:0032876657
SN - 0193-1849
VL - 277
SP - E316-E324
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 2 40-2
ER -