Abstract
Oxidative stress in adipose tissue plays an etiological role in a variety of obesity-related metabolic disorders. We previously reported that increased adipose tissue 4-hydroxynonenal (4-HNE) contents contributed to obesity-related plasma adiponectin decline in mice. In the present study, we investigated the effects of intracellular 4-HNE accumulation on lipolytic response in adipocytes/adipose tissues and underlying mechanisms. In both fully-differentiated 3T3-L1 and primary adipocytes, a 5-hour 4-HNE exposure elevated lipolytic reaction in a dose-dependent manner at both basal and isoproterenol-stimulated conditions, evidenced by significantly increased glycerol and fatty acids releases. This conclusion was corroborated by the comparable observations when the minced human visceral adipose tissues were used. Mechanistic investigations revealed that 4-HNE-stimulated lipolytic activation is multifactorial. 4-HNE exposure quickly increased intracellular cyclic AMP (cAMP) level, which was concomitant with increased phosphorylations of protein kinase A (PKA) and its direct downstream target, hormone sensitive lipase (HSL). Pre-incubation with H89, a potent PKA inhibitor, prevented 4-HNE stimulated glycerol release, suggesting that enhanced lipolytic action in response to 4-HNE increase is mediated mainly by cAMP/PKA signal pathway in adipocytes. In addition to activating cAMP/PKA/HSL pathway, 4-HNE exposure also suppresses AMP-activated protein kinase (AMPK), a suppressive pathway for lipolysis, measured by both Western blotting for phosphorylated form of AMPK and ELISA for enzyme activity. Furthermore, 5-Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR), a pharmacological AMPK activator, alleviated 4-HNE-induced lipolysis, suggesting that AMPK suppression also contributes to 4-HNE elicited lipolytic response. In conclusion, our findings indicate that increased intracellular 4-HNE accumulation in adipocytes/adipose tissues contributes to obesity-related lipolytic activation.
Highlights
Adipose tissue plays a critical role in the regulation of whole body energy homeostasis
We previously reported that the obesity induced by long-term high-fat diet feeding was associated with increased adipose tissue 4-HNE
Intracellular fat contents in adipocytes are positively associated with lipid peroxidation. 4-HNE is one of the most abundant and reactive aldehydic products derived from peroxidation of n-6 polyunsaturated fatty acids [15,16,17]
Summary
Adipose tissue plays a critical role in the regulation of whole body energy homeostasis. Excess energy is stored in adipocytes in the form of triglycerides (TG) and mobilized via a process named lipolysis in the form of free fatty acids (FFAs) and glycerol, which are used for energy requirement of other organs. The pathways controlling these pathways are highly regulated. A variety of hormones regulate lipolytic process in adipose tissue and general intracellular regulatory systems are well characterized [1,2]. The major hormones stimulating lipolysis are catecholamines. Catecholamines-induced the MEK- extracellular signal-regulated kinases 1 and 2 (ERK1/2)
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