Hyperleptinemia contributes to antipsychotic drug-associated obesity and metabolic disorders

Abstract

Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution of this hyperleptinemia to weight gain and metabolic deterioration has not been defined. Here, with an established mouse model that recapitulates antipsychotic drug-induced obesity and insulin resistance, we not only confirm that hyperleptinemia occurs before weight gain but also demonstrate that hyperleptinemia contributes directly to the development of obesity and associated metabolic disorders. By suppressing the rise in leptin through the use of a monoclonal leptin-neutralizing antibody, we effectively prevented weight gain, restored glucose tolerance, and preserved adipose tissue and liver function in antipsychotic drug-treated mice. Mechanistically, suppressing excess leptin resolved local tissue and systemic inflammation typically associated with antipsychotic drug treatment. We conclude that hyperleptinemia is a key contributor to antipsychotic drug-associated weight gain and metabolic deterioration. Leptin suppression may be an effective approach to reducing the undesirable side effects of antipsychotic drugs.

Figure 1.. Effect of acute olanzapine and risperidone treatment on body weight, food intake, and circulating leptin

Female mice (n = 5 per group) were placed on a high-fat diet alone (Ctrl) or a high-fat diet supplemented with olanzapine or risperidone for 2 weeks. Body weight, food intake, and circulating leptin concentrations were measured at the indicated time points. At the end of the experiment, subcutaneous adipose tissue (SAT) and gonadal adipose tissue (GAT) were collected for gene expression analysis. (A) Body weight; (B) food intake; (C) circulating leptin; (D) leptin gene expression in SAT; (E) adiponectin gene expression in SAT; (F) F4/80 expression in SAT; (G) leptin expression in GAT; (H) adiponectin gene expression in GAT; (I) F4/80 expression in GAT. Data are mean ± SEM. Student’s t test or one-way ANOVA: *p < 0.05, **p < 0.01, ***p < 0.001 for olanzapine vs Ctrl or risperidone vs Ctrl.

Figure 2.. Effect of risperidone and risperidone + LepAb on body weight, food intake, and glucose tolerance

Female mice (n = 9) were placed on a high-fat diet alone (Ctrl) or a high-fat diet supplemented with risperidone. Mice were treated with either control IgG or LepAb twice weekly. Body weight and food intake were measured. Glucose tolerance was measured by a glucose tolerance test (GTT) at the end of the experiment. (A) Body weight; (B) daily food intake; (C) cumulative food intake; (D) glucose tolerance. A second cohort of female mice (n = 8 per group) were placed on HFD plus risperidone diet for 4 weeks to achieve significant obesity. The mice were then injected with IgG or LepAb for another 8 weeks. (E) Body weight; (F) Daily food intake; (G) Food accumulation; (H) OGTT. Data are mean ± SEM. Student’s t test or one-way ANOVA: *p < 0.05, **p < 0.01, ***p < 0.001 for risperidone + IgG vs Ctrl diet + IgG; ^# p < 0.05, ^##p < 0.01, ^###p < 0.001 for risperidone + LepAb vs risperidone + IgG.

Figure 3.. Circulating leptin, adiponectin, and insulin concentrations in response to risperidone and risperidone + LepAb treatment

(A) Leptin expression in SAT; (B) leptin expression in GAT; (C) circulating leptin; (D) adiponectin expression in SAT; (E) adiponectin expression in GAT; (F) circulating adiponectin; and (G) circulating insulin in the fed state. Data are mean ± SEM. Student’s t test: *p < 0.05, **p < 0.01, ***p < 0.001 for risperidone + IgG vs Ctrl diet + IgG; ^#p < 0.05, ^##p < 0.01, ^###p < 0.001 for risperidone + LepAb vs risperidone + IgG.

Figure 4.. Effects of risperidone and risperidone + LepAb on liver and brown adipose tissue function

(A) Col1a1 expression in liver; (B) Col4a4 expression in liver; (C) Acta2 expression in liver; (D) Trichrome staining of liver; (E) Prdm16 expression in brown fat; (F) Pgc1a expression in brown fat; (G) Ucp1 expression in brown fat; (H) H&E staining of brown fat. Data are mean ± SEM. Student’s t test: *p < 0.05, **p < 0.01, ***p < 0.001 for risperidone + IgG vs Ctrl diet + IgG; ^#p < 0.05, ^##p < 0.01, ^###p < 0.001 for risperidone + LepAb vs risperidone + IgG.

Figure 5.. Adipose tissue and systemic inflammation in response to risperidone and risperidone + LepAb

(A) Adgre1 expression in GAT; (B) Mcp1 expression in GAT; (C) Ccl4 expression in GAT; (D) Mac2 staining in GAT; (E) circulating MCP1; (F) circulating IL-1β; (G) circulating TNFα. Data are mean ± SEM. Student’s t test: *p < 0.05, **p < 0.01, ***p < 0.001 for risperidone + IgG vs Ctrl diet + IgG; ^#p < 0.05, ^##p < 0.01, ^###p < 0.001 for risperidone + LepAb vs risperidone + IgG.

Figure 6.. Effects of risperidone and risperidone + LepAB on hypothalamic gene expression

(A) Agrp expression; (B) Npy expression; (C) Pomc expression; (D) Mcp1 expression; (E) Ccl8 expression; (F) Adgre1 expression. Data are mean ± SEM. Student’s t test: *p < 0.05, **p < 0.01, ***p < 0.001 for risperidone + IgG vs Ctrl diet + IgG; ^#p < 0.05, ^##p < 0.01, ^###p < 0.001 for risperidone + LepAB vs risperidone + IgG.

Figure 7.. Risperidone induces mammary gland development

(A) H&E staining of SAT; (B) CD31/Mac2 staining of mammary duct-like structures in mouse SAT. CD31 stained as “green” and Mac2 stained as “red”; (C). Prolactin concentrations. Data are mean ± SEM. Student’s t test: *p < 0.05, **p < 0.01, ***p < 0.001 for risperidone + IgG vs Ctrl diet + IgG; ^#p < 0.05, ^##p < 0.01, ^###p < 0.001 for risperidone + LepAb vs risperidone + IgG.