Altered Levels of Adiponectin and Adiponectin Receptors May Underlie the Effect of Ciliary Neurotrophic Factor (CNTF) to Enhance Insulin Sensitivity in Diet-induced Obese Mice

Introduction

Ciliary neurotrophic factor (CNTF), a neuronal growth factor originally studied in amyotrophic lateral sclerosis, induces weight loss and improves insulin resistance in humans and rodents [1]. It has been recently shown that CNTF induces hypothalamic neurogenesis and that it signals through the CNTFRα-IL-6R-gp130β receptor complex to increase fatty-acid oxidation and to reduce insulin resistance in skeletal muscle by activating AMP-activated protein kinase (AMPK) in peripheral tissues [2] [3] [4].

Adiponectin, a hormone secreted by adipose tissue, controls glucose and lipid metabolism, prevents hepatic steatosis, and plays an important role in the regulation of insulin resistance and energy homeostasis by binding and activating two cell membrane receptors. Adiponectin receptor 1 (AdipoR1) is most abundantly expressed in muscle, and adiponectin receptor 2 (AdipoR2), most predominantly in liver [5]. The adiponectin receptors can ligand-dependently and dose-dependently activate AMPK, p38 mitogen-activated protein kinase, and PPARa, thus stimulating fatty-acid oxidation and glucose uptake in hepatocytes and myocytes, limiting deposition of fat, and maintaining insulin responsiveness in liver and muscle. In addition, the weight-reducing effects of CNTF appear to result from direct effects on skeletal muscle and may not require central signaling, in contrast to the effects of leptin [3] [4].

Although accumulating evidence suggests that adiponectin and its receptors play an important role in obesity and insulin resistance, no previous study has investigated whether administration of CNTF_Ax15 may improve insulin resistance by altering expression of adiponectin and its receptors above and beyond what would be expected based on reduction of caloric intake or body weight alone. We hypothesize that the effect of CNTF_Ax15 on insulin resistance could be mediated, in part, through alterations of secretion and expression patterns of adiponectin and its receptors. Therefore, we studied the effect of treatment with CNTF_Ax15 vs. placebo treatment and hypocaloric pair feeding for 7 days on circulating adiponectin and leptin levels as well as expression patterns of adiponectin and its receptors in white adipose tissue, liver, and muscle in insulin- and leptin-resistant, hyperinsulinemic diet-induced obese (DIO) C57Bl/6J mice, the mouse model most closely associated with human obesity [1].

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1 These authors contributed equally to this work.

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