Adiponectin is critical in determining susceptibility to depressive behaviors and has antidepressant-like activity

Abstract

Depression is a debilitating mental illness and is often comorbid with metabolic disorders such as type 2 diabetes. Adiponectin is an adipocyte-derived hormone with antidiabetic and insulin-sensitizing properties. Here we show that adiponectin levels in plasma are reduced in a chronic social-defeat stress model of depression, which correlates with decreased social interaction time. A reduction in adiponectin levels caused by haploinsufficiency results in increased susceptibility to social aversion, "anhedonia," and learned helplessness and causes impaired glucocorticoid-mediated negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis. Intracerebroventricular (i.c.v.) injection of an adiponectin neutralizing antibody precipitates stress-induced depressive-like behavior. Conversely, i.c.v. administration of exogenous adiponectin produces antidepressant-like behavioral effects in normal-weight mice and in diet-induced obese diabetic mice. Taken together, these results suggest a critical role of adiponectin in depressive-like behaviors and point to a potential innovative therapeutic approach for depressive disorders.

Fig. 1.

Chronic social defeat reduces circulating adiponectin concentrations. (A) Timeline of the experimental procedure. D1–16, day1–16; SI, social interaction; DEXA, dual energy X-ray absorptiometry. (B) Chronic social defeat (CSD) for 14 consecutive days induces reduction of social interaction time (Left; F_(3,72) = 8.914, P < 0.001) and decreases total plasma levels of adiponectin (Center; t₍₃₆₎ = 6.239, P < 0.0001). Nondefeat control, n = 16; CSD, n = 22. **P < 0.01, ***P < 0.001 compared with their respective no target conditions; ^###P < 0.001 compared control mice in the presence of a social target. There is a significant correlation between total plasma adiponectin levels and social interaction ratio (time spent in the interaction zone in the presence of a social target/ time spent in interaction zone without a social target) (r = 0.56; P < 0.001). (C) Analysis of the oligomeric complex distribution of adiponectin. (Upper) Representative distribution of adiponectin oligomeric complexes from socially defeated mice in comparison with nondefeated control mice. Adiponectin was separated by gel filtration chromatography followed by immunoblotting. (Lower) Concentrations of oligomeric complexes of adiponectin in plasma that was calculated on the basis of the relative ratio of adiponectin oligomeric complexes revealed by gel filtration and total adiponectin levels quantified by ELISA. CSD decreases relative levels of HMW (t₍₈₎ = 2.583: P < 0.05) and hexamers (t₍₈₎ = 3.420, P < 0.01) without affecting trimers (t₍₈₎ = 0.5851, P > 0.5). n = 5 per group. (D) Body weight and body composition measured by DEXA at the end of the experiments. CSD has no significant effect on body weight (t₍₁₄₎ = 1.438 P = 0.172), fat mass (t₍₁₄₎ = 0.5138, P = 0.615) or lean mass (t₍₁₄₎ = 0.5682, P = 0.579). n = 8 per group. All data are expressed as mean ± SEM.

Fig. 2.

Adiponectin haploinsufficiency increases susceptibility to stress-induced depression-like behaviors. (A, Left) Total plasma adiponectin levels in Adipo^+/− mice and wild-type littermates. n = 5–6 per group. ***P < 0.001. (Right) Adiponectin oligomers as determined by gel elctrophoresis under nonreducing and nonheat-denaturing conditions. (B) Locomotor activity. There is no significant difference in locomotor performance within 2 h between Adipo^+/− mice and wild-type littermate controls (F_(1,188) = 0.073, P = 0.788). n = 8 per group. (C) Social-defeat–induced social withdrawal. Left graph, nondefeated Adipo^+/− mice and wild-type littermate mice show no difference in social interaction measured at 0, 4, and 14 d after housing in cages identical to defeated mice (genotype F_(1,82) = 0.004, P = 0.948; target F_(1,82) = 7.350, P < 0.01; time F_(2,82) = 1.752, P = 0.180; genotype × target F_(1,82) = 0.282, P = 0.597; genotype × time F_(2,82) = 0.0128, P = 0.987; genotype × target × time F_(2,82) = 0.449, P = 0.956). Center graph and image, Adipo^+/− mice display significant social aversion following 4 d of social defeat (genotype F_(1,48) = 15.384, P < 0.001; target F_(1,48) = 17.194, P < 0.001; genotype × target F_(1,48) = 4.860, P < 0.05). Right graph, both Adipo^+/− mice and wild-type littermate controls exhibit social aversion after 14 d of social defeat (genotype F_(1,38) = 0.008, P = 0.929; target F_(1,38) = 20.486, P < 0.001; genotype × target F_(1,38) = 0.108, P = 0.744). Nondefeat control n = 7–9 per group; defeat, n = 10–15 per group. **P < 0.01 compared with the respective no-target conditions; ^##P < 0.01 compared with wild-type littermates with the presence of a target. (D) Social-defeat–induced anhedonia. Adipo^+/− mice show significant reduction in sucrose preference following social-defeat stress (genotype F_(1,46) = 6.785, P = 0.01; defeat F_(2,46) = 4.936, P = 0.01). n = 8–9 per group. *P < 0.05, **P < 0.01 compared with presocial-defeat conditions. (E) Inescapable foot-shock–induced learned helplessness. There are significant effects of genotype, shock stress, and genotype × shock stress interaction on escape latency (Left, genotype F_(1,32) = 4.248, P < 0.05; shock stress F_(1,32) = 25.015, P < 0.001; genotype × stress interaction F_(1,32) = 5.636, P < 0.05) and number of failure to escape (Right, genotype F_(1,32) = 4.545, P < 0.05; shock stress F_(1,32) = 20.831, P < 0.001; genotype × stress interaction F_(1,32) = 4.545, P < 0.05). Wild-type, n = 6 for nonshock and n = 10 for shock treatment; Adipo^+/−, n = 8 for nonshock and n = 12 for shock treatment. *P < 0.05, **P < 0.01 compared with wild-type littermates exposed to foot-shock stress. All data are expressed as mean ± SEM.

Fig. 3.

Adiponectin haploinsufficiency results in resistance to glucocorticoid-induced feedback inhibition of hypothalamic–pituitary–adrenal axis. (A) Dexamethasone (DEX) suppression test. DEX-induced suppression of corticosterone secretion is impaired in Adipo^+/− mice (treatment F_(1,30) = 8.394, P < 0.01; genotype F_(1,30) = 14.176, P < 0.001; treatment × genotype F_(1,30) = 3.366; P = 0.077). Wild-type, n = 10 for basal and n = 9 for DEX treatment; Adipo^+/−, n = 10 for basal and n = 7 for DEX treatment. *P < 0.05 compared with basal levels. (B) Combined DEX/CRH test. Adipo^+/− mice show enhanced corticosterone response to CRH challenge (F_(1,40) = 12.303, P = 0.001). Wild-type, n = 10; Adipo^+/−, n = 11. *P < 0.05, **P < 0.01 compared with wild-type littermate controls. All data are expressed as mean ± SEM.

Fig. 4.

Central adiponectin action modulates depression-like behaviors. (A) In situ hybridization showing expression patterns of AdipoR1 and AdipoR2 mRNA in the forebrain. mPFC, medial prefrontal cortex; Hipp, hippocampus; Amy, amygdala. (B) Effect of endogenous adiponectin in the brain on defeat-induced social aversion. Mice received i.c.v. injection of monoclonal adiponectin antibody (0.6 μg) or normal IgG 1 h before each social-defeat episode and exhibited significant social aversion after 4 d of social defeat (F_(3,36) = 3.766, P < 0.05). n = 10 per group. ^#P = 0.01 compared with the no-target condition; *P < 0.01 compared with control mice received normal IgG. (C) Antidepressant-like properties of i.c.v. infusion of globular adiponectin (gAd) in normal chow-diet–fed mice at 9–11 wk of age. I.c.v. injection of globular adiponectin decreases immobility time in the forced swim test (Left; control n = 16, gAd (0.1 μg) n = 10, gAd (0.3 μg) n = 16; F_(2,39) = 3.236, P < 0.05) and the tail suspension test (Center; control n = 18, gAd (0.1 μg) n = 9, gAd (0.3 μg) n = 16; F_(2,40) = 9.267, P < 0.001). *P < 0.05, **P < 0.01) compared with vehicle-treated control mice without affecting locomotor activity measured in the home cage (Right, control n = 14, gAd (0.1 μg) n = 8, gAd (0.3 μg) n = 13; F_(2,32) = 0.238, P = 0.789). (D) Antidepressant-like effect of i.c.v. infusion of full-length adiponectin (fAd) in normal chow diet (NC) or high-fat diet (HFD)-fed mice. Left, i.c.v. injection of full-length adiponectin (1 µg) significantly decreases immobility time in the forced swim test in NC fed mice at 9–11 wk of age (t₍₁₄₎ = 2.503, P < 0.05; n = 8 per group). *P < 0.05 compared with vehicle (veh)-treated controls. Center, i.c.v. infusion of fAd (1 μg) produces a significant reduction in immobility in the forced swim test in HFD (60% of kcal from fat)-fed mice at 4 wk of age for 16 wk (Left, t₍₁₇₎ = 3.397, P < 0.01; n = 9–10 per group) without affecting locomotor activity measured in an open box (Right, t₍₈₎ = 0.0531, P = 0.959; n = 5 per group). ^#P < 0.05 compared with vehicle (Veh)-treated NC-fed mice; **P < 0.01 compared with Veh-treated HFD-fed mice. All data are expressed as mean ± SEM.