Abstract
The adipocyte-derived hormone adiponectin has a broad spectrum of functions beyond metabolic control. We previously reported that adiponectin acts in the brain to regulate depression-related behaviors. However, its underlying neural substrates have not been identified. Here we show that adiponectin receptor 1 (AdipoR1) is expressed in the dorsal raphe nucleus (DRN) and colocalized with tryptophan hydroxylase 2 (TPH2), a marker of serotonin (5-HT) neurons. Selective deletion of AdipoR1 in 5-HT neurons induced anhedonia in male mice, as indicated by reduced female urine sniffing time and saccharin preference, and behavioral despair in female mice and enhanced stress-induced decrease in sucrose preference in both sexes. The expression levels of TPH2 were downregulated with a concurrent reduction of 5-HT-immunoreactivity in the DRN and its two major projection regions, the hippocampus and medial prefrontal cortex (mPFC), in male but not female mice lacking AdipoR1 in 5-HT neurons. In addition, serotonin transporter (SERT) expression was upregulated in both DRN projection fields of male mice but only in the mPFC of female mice. These changes presumably lead to decreased 5-HT synthesis and/or increased 5-HT reuptake, thereby reducing 5-HT transmission. The augmented behavioral responses to the selective serotonin reuptake inhibitor fluoxetine but not desipramine, a selective norepinephrine reuptake inhibitor, observed in conditional knockout male mice supports deficient 5-HT transmission underlying depression-related phenotypes. Our results indicate that adiponectin acts on 5-HT neurons through AdipoR1 receptors to regulate depression-related behaviors in a sex-dependent manner.
Highlights
Adiponectin is a hormone secreted almost exclusively by adipocytes [1, 2]
While adiponectin receptor 1 (AdipoR1) mRNA was highly expressed in the dorsal raphe nucleus (DRN), AdipoR2 mRNA was present in very low abundance (Fig. 1a)
We found that the vast majority of 5-HT neurons immunoreactive for tryptophan hydroxylase 2 (TPH2) expressed AdipoR1 mRNA in both male and female mice (Fig. 1b; male mice, 97.40% ± 1.33%, total 1289 neurons counted from six brain sections; female mice, 98.80% ± 0.40%, total 1356 neurons counted from six brain sections)
Summary
Adiponectin is a hormone secreted almost exclusively by adipocytes [1, 2]. Full-length adiponectin is the predominant circulating form and can be found as a trimer, hexamer, or high-molecular weight oligomer [5, 6]. Multiple lines of evidence indicate that adiponectin enters the brain from circulation. Trimeric and hexameric forms of adiponectin can be found in the cerebrospinal fluid (CSF) of humans and animals [7,8,9,10] and intravenous injection of adiponectin increases CSF adiponectin levels [10, 11]. Adiponectin can be detected in the CSF of homozygous adiponectin-deficient mice after intravenous injection of full-length adiponectin, indicating that adiponectin can cross the blood–brain barrier [9, 12]
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