ABSTRACT
Insulin stimulates glucose uptake into adipocytes via mTORC2/AKT signaling and GLUT4 translocation and directs glucose carbons into glycolysis, glycerol for TAG synthesis, and de novo lipogenesis. Adipocyte insulin resistance is an early indicator of type 2 diabetes in obesity, a worldwide health crisis. Thus, understanding the interplay between insulin signaling and central carbon metabolism pathways that maintains adipocyte function, blood glucose levels, and metabolic homeostasis is critical. While classically viewed through the lens of individual enzyme-substrate interactions, advances in mass spectrometry are beginning to illuminate adipocyte signaling and metabolic networks on an unprecedented scale, yet this is just the tip of the iceberg. Here, we review how 'omics approaches help to elucidate adipocyte insulin action in cellular time and space.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin , Adipocytes/metabolism , Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Humans , Insulin/metabolism , Signal TransductionABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
An increased activity of the hypothalamo-pituitary-adrenal axis resulting in exaggerated glucocorticoid secretion has been repeatedly described in patients with diabetes mellitus and in animal models of this disease. However, it has been pointed out that experimental diabetes is accompanied by a decreased glucocorticoid response to ACTH stimulation. Because previous studies from our laboratory demonstrate the involvement of nitric oxide (NO) in the modulation of corticosterone production, present investigations were designed to evaluate 1) the impact of streptozotocin (STZ)-induced diabetes on the adrenocortical nitrergic system and 2) the role of NO in the modulation of adrenal steroidogenesis in STZ-diabetic rats. Four weeks after STZ injection, increased activity and expression levels of proteins involved in L-arginine transport and in NO synthesis were detected, and increased levels of thiobarbituric acid reactive species, carbonyl adducts, and nitrotyrosine-modified proteins were measured in the adrenocortical tissue of hyperglycemic rats. An impaired corticosterone response to ACTH was evident both in vivo and in adrenocortical cells isolated from STZ-treated animals. Inhibition of NO synthase activity resulted in higher corticosterone generation in adrenal tissue from STZ-treated rats. Moreover, a stronger inhibition of steroid output from adrenal cells by a NO donor was observed in adrenocortical Y1 cells previously subjected to high glucose (30 mM) treatment. In summary, results presented herein indicate an inhibitory effect of endogenously generated NO on steroid production, probably potentiated by hyperglycemia-induced oxidative stress, in the adrenal cortex of STZ-treated rats.
Subject(s)
Adrenal Cortex/physiopathology , Corticosterone/metabolism , Diabetes Mellitus, Experimental/metabolism , Nitric Oxide/physiology , Streptozocin , Adrenal Cortex/drug effects , Adrenal Cortex/metabolism , Adrenocorticotropic Hormone/pharmacology , Animals , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/physiopathology , Glucose/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Male , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/metabolism , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolism , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/metabolism , Pituitary-Adrenal System/physiopathology , Rats , Rats, WistarABSTRACT
The present study was designed to investigate the effect of lipopolysaccharide (LPS) on the expression levels and activities of the nitric oxide synthase (NOS) and heme oxygenase (HO) systems in the rat adrenal gland. Both enzymatic activities were significantly increased in this tissue after in vivo treatment with LPS. The concurrent induction of the HO-1, NOS-1, and NOS-2 gene products was also detected as both mRNAs and protein levels were augmented by this treatment in a time-dependent way. A significant interaction between both signaling systems was also demonstrated as in vivo blockage of NOS activity with N(G)-nitro-L-arginine methyl ester (L-NAME) resulted in a significant reduction in HO expression and activity levels, while an increase in NOS activity was observed when HO was inhibited by Sn-protoporphyrin IX (Sn-PPIX). As both NOS and HO activities have been previously involved in the modulation of adrenal steroidogenesis, we investigated the participation of these signaling systems in the adrenal response to LPS. Our results showed that acute stimulation of steroid production by ACTH was significantly increased when either NOS or HO activities were inhibited. We conclude that adrenal NOS and HO can be induced by a non-lethal dose of endotoxin supporting a modulatory role for these activities in the adrenal response to immune challenges.
