Year

2014

Degree Name

Doctor of Philosophy

Department

School of Medicine

Abstract

Second-generation antipsychotics (SGAs), including olanzapine, have been used widely in the clinic to treat schizophrenia and other psychotic disorders; however, the metabolic side-effects associated with SGA treatments, including weight gain, hyperphagia and elevated adiposity, have resulted in reduction of drug compliance and severe co-morbidities. Both clinical and animal studies have revealed that olanzapine-induced body weight gain has three typical stages. Using a female rat model, this study investigated the mechanisms underlying the alterations in food intake, brown adipose tissue (BAT) thermogenesis and inflammation responses in these three stages of olanzapine-induced weight gain.

The aim of Chapter 2 was to examine the role of the hypothalamic ghrelin signalling pathway in olanzapine-induced hyperphagia. Female Sprague-Dawley rats were orally treated with olanzapine (1mg/kg) or vehicle three times daily by self-administration of a sweet cookie-dough for 1 week, 2 weeks and 5 weeks, representing short-, mid- and long-term of olanzapine treatment, respectively. Olanzapine-induced body weight gain was evidenced throughout the three treatment cohorts, while elevated daily food intake and circulating ghrelin levels, as well as most of the hypothalamic ghrelin signalling parameters, including FOXO1, BSX, pCREB, NPY, AgRP and POMC, were altered towards the direction in favouring hyperphagia in the short-term treatment cohort only. In addition, olanzapine-induced weight gain was vanished by restricting food intake to the level of control, suggesting food intake is the main contributing factor for body weight gain under short-term olanzapine treatment. Furthermore, ICV injection of a ghrelin antagonist (D-Lys-GHRP-6) completely blocked the effect of olanzapine on elevating food intake and the alterations of the expressions of downstream hypothalamic ghrelin signalling parameters, suggesting hypothalamic ghrelin signalling plays a critical role in mediating hyperphagia under short-term olanzapine treatment.

Following on the effects of olanzapine on body weight gain observed in the mid to long-term without changes in food intake, Chapter 3 aimed to investigate the role of BAT thermogenesis and locomotor activity (two important components of energy expenditure), during the prolonged periods of olanzapine treatments. The results showed that long-term olanzapine treatment (from day 18 to 34) induced a significant reduction in BAT temperature, with an acute effect being observed between 45 and 150 minutes post-treatment in the long-term cohort. This reduction in BAT temperature in the long-term cohort was associated with decreased expressions of UCP1 and PGC-1α in BAT. Further, TH mRNA expressions in hypothalamus and brainstem were both downregulated by olanzapine treatment in the mid-to long-term, accompanied by a reduction in percentage brown adipocytes in BAT. These findings suggest that reduced BAT thermogenesis through downregulation of central sympathetic signals may play a role in long-term olanzapine-induced weight gain. Finally, locomotor activity was reduced by olanzapine during the three treatment periods examined, suggesting a potential role in the entire olanzapine treatment courses.

Emerging evidence from the literature has suggested the association between obesity, in particular adiposity, and low-grade inflammation in the hypothalamus and the periphery. Therefore, Chapter 4 investigated the inflammatory effects of olanzapine through the three stages of treatment, as well as their relationship with adiposity and body weight gain. Olanzapine increased average adipocyte size in visceral WAT, which was highly correlated with elevations of macrophage infiltration, with the level of macrophage infiltration increased over time. In addition, olanzapine also lead to elevation of macrophage infiltration in BAT, but not liver. Furthermore, pro-inflammation cytokines TNFα, IL-1β, and IL-6 were upregulated by olanzapine in hypothalamus, WAT, BAT, but not liver. Consistent with the elevation in visceral adiposity (adipose tissue weight), plasma triglycerides, but not total, HDL, or LDL cholesterol levels, were elevated by olanzapine throughout the three treatment cohorts. These findings suggest a close relationship between adiposity and low-grade inflammation under olanzapine treatment. Moreover, time-related development of low-grade inflammation along the time courses of olanzapine treatment is also suggested.

In conclusion, this thesis revealed novel mechanisms involving alterations of the hypothalamic ghrelin signalling affecting food intake, BAT thermogenesis and locomotor activity, and inflammation responses during the three typical stages of olanzapine-induced weight gain. In the short-term of olanzapine treatment, elevated food intake is the main contributor for body weight gain. In this stage, hypothalamic ghrelin signalling mediates the hyperphagic effect of olanzapine, which can be blocked by central administration of a ghrelin receptor antagonist. Reduced locomotor activity and mild elevation of inflammatory responses are also evidenced at this stage. In the mid-term of olanzapine treatment, the elevated food intake starts to vanish, while biochemical and morphological changes in favouring the reduction of BAT thermogenesis begins to be evidenced. At this stage, reduced locomotor activity and the enhanced inflammation responses may be the main contributor to the continued weight gain. During the long-term of olanzapine treatment, when no elevation of food intake is evidenced, the reduced BAT thermogenesis, together with the welldeveloped inflammatory responses, may become the main drive for the maintenance of heavy body weight. Overall, this thesis provides important guidelines for future research in developing new pharmacological targets with improved metabolic side-effects.

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