Central Adiponectin Acutely Improves Glucose Tolerance in Male Mice

Abstract

Adiponectin, an adipocyte-derived hormone, regulates glucose and lipid metabolism. It is also antiinflammatory. During obesity, adiponectin levels and sensitivity are reduced. Whereas the action of adiponectin in the periphery is well established the neuroendocrine role of adiponectin is largely unknown. To address this we analyzed the expression of adiponectin and the 2 adiponectin receptors (AdipoR1 and AdipoR2) in response to fasting and to diet-induced and genetic obesity. We also investigated the acute impact of adiponectin on central regulation of glucose homeostasis. Adiponectin (1 μg) was injected intracerebroventricularly (ICV), and glucose tolerance tests were performed in dietary and genetic obese mice. Finally, the influence of ICV adiponectin administration on central signaling cascades regulating glucose homeostasis and on markers of hypothalamic inflammation was assessed. Gene expression of adiponectin was down-regulated whereas AdipoR1 was up-regulated in the arcuate nucleus of fasted mice. High-fat (HF) feeding increased AdipoR1 and AdipoR2 gene expression in this region. In mice on a HF diet and in leptin-deficient mice acute ICV adiponectin improved glucose tolerance 60 minutes after injection, whereas normoglycemia in control mice was unaffected. ICV adiponectin increased pAKT, decreased phospho-AMP-activated protein kinase, and did not change phospho-signal transducer and activator of transcription 3 immunoreactivity. In HF-fed mice, ICV adiponectin reversed parameters of hypothalamic inflammation and insulin resistance as determined by the number of phospho-glycogen synthase kinase 3 β(Ser9) and phospho-c-Jun N-terminal kinase (Thr183/Tyr185) immunoreactive cells in the arcuate nucleus and ventromedial hypothalamus. This study demonstrates that the insulin-sensitizing properties of adiponectin are at least partially based on a neuroendocrine mechanism that involves centrally synthesized adiponectin.

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

“…Interestingly, when cells were overexposed to insulin and adiponectin, the insulin-dependent Akt and ERK1/2 phosphorylations were totally restored. This agreed with previous studies demonstrating an adiponectin-dependent improvement of both hypothalamic and peripheral insulin sensitivity (27,31). Importantly, the insulin-sensitizing effects of adiponectin were abolished in APPL1-suppressed SH-SY5Y cells, presenting the first evidence for the critical role of APPL1 in neuronal adiponectin/insulin cross talk and in mediating the insulin-sensitizing effect of adiponectin.…”

“…Recent studies have reported that adiponectin is crucially involved in hypothalamic control of energy homeostasis (29,30). Additionally, central adiponectin improves glucose tolerance and reverses hypothalamic inflammation and insulin resistance in obese mice (31,32). These data demonstrate that the insulin-sensitizing properties of adiponectin are at least partially related to a neuroendocrine mechanism that involves central action of adiponectin.…”

Long‐lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high‐fat diet on metabolic function and energy expenditure

“…Recent in vivo studies have uncovered beneficial effects of adiponectin treatment on metabolic function. In male mice fed HFD, intracerebroventricular administration of adiponectin led to improved glucose homeostasis and reduced inflammatory signaling (Koch et al ., 2014). The increase in adiponectin levels has been well established in long‐lived mice such as Ames dwarf (Wang et al ., 2006), Snell dwarf (Brooks et al ., 2007) and GHR‐KO (Berryman et al ., 2004) mice.…”

Traveling from the hypothalamus to the adipose tissue: The thermogenic pathway

“…More recent data demonstrate that BMP8B acts by decreasing AMPK in VMH neurons connected to the LHA through glutamatergic fibers that stimulate the orexin (OX) system which in turn activate the SNS promoting thermogenesis in BAT and WAT [81]. Conversely, adiponectin (ADP) and resistin (RSTN) caused a decrease in BAT thermogenesis by activation of hypothalamic AMPK [85], [86], [87], [88], [89], [90], [91], although the role of the VMH in these actions remains unproven. Additional peripheral signals that act on the hypothalamus eliciting sympathetic firing to BAT and activating thermogenesis include amylin and uroguanylin (UGN), with UGN also inducing browning of WAT [92], [93], [94].…”