Adiponectin modulates ventral tegmental area dopamine neuron activity and anxiety-related behavior through AdipoR1

Abstract

Adiponectin, a metabolic hormone secreted by adipocytes, can cross the blood-brain barrier to act on neurons in different brain regions, including those involved in stress-related disorders. Here we show that dopamine neurons in the ventral tegmental area (VTA) express adiponectin receptor 1 (AdipoR1). Intra-VTA infusion of adiponectin or the adiponectin mimetic AdipoRon in wild-type mice decreases basal dopamine neuron population activity and firing rate and reverses the restraint stress-induced increase in dopamine neuron activity and anxiety behavior. Adiponectin haploinsufficiency leads to increased dopamine neuron firing and anxiety behavior under basal conditions. Ablation of AdipoR1 specifically from dopamine neurons enhances neuronal and anxiogenic responses to restraint stress. The effects of intra-VTA infusion of adiponectin on neuronal activity and behavior were abolished in mice lacking AdipoR1 in dopamine neurons. These observations indicate that adiponectin can directly modulate VTA dopamine neuron activity and anxiety behavior, and that AdipoR1 is required for adiponectin-induced inhibition of dopamine neurons and anxiolytic effects. These results strengthen the idea of adiponectin as a key biological factor that links metabolic syndrome and emotional disorders.

Modulation of depression-related behaviors by adiponectin AdipoR1 receptors in 5-HT neurons

“…We have previously shown that adiponectin haploinsufficiency causes depression-and anxiety-related behaviors in mice via a central mechanism of action [21,24]. The present study provides evidence of 5-HT neurons as a neuronal substrate mediating the effects of adiponectin/ AdipoR1 signaling on depression-but not anxiety-related behaviors.…”

“…Radioactive in situ hybridization for detecting AdipoR1 and AdipoR2 gene expression patterns were performed as previously described [21,24]. Briefly, the brain tissue (fresh frozen) was cut at a thickness of 20 μm, mounted onto polylysine coated slides and sequentially fixed in 4% paraformaldehyde for 1 h followed by a rinse in 2× saline sodium citrate (SSC) buffer (300 mM NaCl, 30 mM Na citrate, pH 7.2), acetylated in 0.1 M triethanolamine (pH 8.0) with 0.25% (vol/vol) acetic anhydride for 10 min and dehydrated through a graded series of alcohol (50-100%).…”

“…To examine whether AdipoR1 mRNA is colocalized with 5-HT neurons in the DRN, we performed in situ hybridization to detect AdipoR1 mRNA in combination with immunohistochemistry to detect TPH2, a marker of 5-HT neurons [24]. Mouse AdipoR1 cDNA fragments were amplified by RT-PCR using the primers as follows: forward: 5′-GGGATGTTCTTCCTGGGCGCGGTGCTCTGCCT-3′ and reverse: 5′-ACTCCTGCTCTTGTCTGCCGGTGCTTGGGA GTGG-3′.…”

“…While AdipoR1 is widely expressed in the brain, AdipoR2 is restricted to only a few brain regions [9,21]. We have shown that AdipoR1 and AdipoR2 signaling in the hippocampus and ventral tegmental area are involved in the regulation of anxiety-related behavior and fear memories in a mouse model of post-traumatic disorder [23,24]. However, the specific roles of AdipoR1 and AdipoR2 in depression-related behaviors and the underlying neural substrates remain to be elucidated.…”

Examining the Potential of Developing and Implementing Use of Adiponectin-Targeted Therapeutics for Metabolic and Cardiovascular Diseases

“…AdipoRON effectively improved insulin sensitivity and restored glucose homeostasis via the activation of AdipoR1-AMPK-PGC1α and AdipoR2-PPARα signaling pathways (162). AdipoRON treatment also mimicked adiponectin's established anti-diabetic effects (163) and ability to enhance cellular capacity for mitigating oxidative-stress (162,164), enhancing lipid/glucose oxidation in mitochondria (162,164), anti-inflammatory responses (162,(164)(165)(166)(167), lifeprolonging effect (162,163), anti-cancer effects (168,169), procell survival and anti-apoptotic effect (170,171), neuronal- (172,173), reno- (174,175), and cardio-/vascular-protective effects (165,(176)(177)(178)(179). However, exciting AdipoRON research in animal models has not been translated to establishment of a drug for human use and the search continues for additional small molecule AdipoR agonists which have little or no toxicity.…”