Abstract
This study tested whether chronic systemic administration of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) could attenuate hyperphagia, reduce lean and fat mass losses, and improve whole-body energy homeostasis in insulin-deficient rats. Male Wistar rats were first rendered diabetic through streptozotocin (STZ) administration and then intraperitoneally injected with AICAR for 7 consecutive days. Food and water intake, ambulatory activity, and energy expenditure were assessed at the end of the AICAR-treatment period. Blood was collected for circulating leptin measurement and the hypothalami were extracted for the determination of suppressor of cytokine signaling 3 (SOCS3) content, as well as the content and phosphorylation of AMP-kinase (AMPK), acetyl-CoA carboxylase (ACC), and the signal transducer and activator of transcription 3 (STAT3). Rats were thoroughly dissected for adiposity and lean body mass (LBM) determinations. In non-diabetic rats, despite reducing adiposity, AICAR increased (∼1.7-fold) circulating leptin and reduced hypothalamic SOCS3 content and food intake by 67% and 25%, respectively. The anorexic effect of AICAR was lost in diabetic rats, even though hypothalamic AMPK and ACC phosphorylation markedly decreased in these animals. Importantly, hypothalamic SOCS3 and STAT3 levels remained elevated and reduced, respectively, after treatment of insulin-deficient rats with AICAR. Diabetic rats were lethargic and displayed marked losses of fat and LBM. AICAR treatment increased ambulatory activity and whole-body energy expenditure while also attenuating diabetes-induced fat and LBM losses. In conclusion, AICAR did not reverse hyperphagia, but it promoted anti-catabolic effects on skeletal muscle and fat, enhanced spontaneous physical activity, and improved the ability of rats to cope with the diabetes-induced dysfunctional alterations in glucose metabolism and whole-body energy homeostasis.
Highlights
Insulin is a key player in the control of intermediary metabolism with widespread effects on food intake, body composition, and whole-body energy homeostasis [1]
STZ and STZ+AICAR rats did not gain any significant amount of weight throughout the study (Figure 1C and D) and feed efficiency was very low in diabetic rats either prior to or during AICAR administration (Figure 1E), demonstrating that the fuel ingested was not diverted towards growth or accretion of fat mass
Hypothalamic AMPK and acetyl-CoA carboxylase (ACC) phosphorylation were markedly increased and AICAR treatment completely reversed this effect; it was not sufficient to prevented hyperphagia in these animals. This was likely due to the fact that while suppressor of cytokine signaling 3 (SOCS3) remained unaltered, signal transducer and activator of transcription 3 (STAT3) content and phosphorylation were markedly reduced in the hypothalami of insulindeficient rats, and these were not altered by AICAR treatment
Summary
Insulin is a key player in the control of intermediary metabolism with widespread effects on food intake, body composition, and whole-body energy homeostasis [1]. Under conditions of insulin deficiency, such as in type 1 diabetes (T1D), a myriad of complex and interactive dysfunctional metabolic alterations take place [2]. Alternative pharmacological approaches have been tested either alone or in combination with insulin in an attempt to improve glycemic control and prevent multiple complications of diabetes [3]. In this context, several studies have investigated the effectiveness of pharmacological agents that activate the cellular energy sensor AMP-activated protein kinase (AMPK) in diabetes therapy [4,5,6]. AMPK is a heterotrimeric enzyme that can be allosterically and covalently [7,8] activated under conditions of metabolic stresses (e.g. exercise, glucose deprivation, etc) that increase intracellular AMP, ADP or Ca2+ [7]
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