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Alterations to melanocortinergic, GABAergic and cannabinoid neurotransmission associated with olanzapine-induced weight gain.

Weston-Green K, Huang XF, Deng C - PLoS ONE (2012)

Bottom Line: Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc.Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY.This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission.

View Article: PubMed Central - PubMed

Affiliation: Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, Australia.

ABSTRACT

Background/aim: Second generation antipsychotics (SGAs) are used to treat schizophrenia but can cause serious metabolic side-effects, such as obesity and diabetes. This study examined the effects of low to high doses of olanzapine on appetite/metabolic regulatory signals in the hypothalamus and brainstem to elucidate the mechanisms underlying olanzapine-induced obesity.

Methodology/results: Levels of pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and glutamic acid decarboxylase (GAD(65), enzyme for GABA synthesis) mRNA expression, and cannabinoid CB1 receptor (CB1R) binding density (using [(3)H]SR-141716A) were examined in the arcuate nucleus (Arc) and dorsal vagal complex (DVC) of female Sprague Dawley rats following 0.25, 0.5, 1.0 or 2.0 mg/kg olanzapine or vehicle (3×/day, 14-days). Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc. GAD(65) mRNA expression increased and CB1R binding density decreased in the Arc and DVC. Alterations to neurotransmission signals in the brain significantly correlated with body weight and adiposity. The minimum dosage threshold required to induce weight gain in the rat was 0.5 mg/kg olanzapine.

Conclusions: Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY. This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission. Metabolic dysfunction can be modelled in the female rat using low, clinically-comparable olanzapine doses when administered in-line with the half-life of the drug.

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Related in: MedlinePlus

Correlations.Correlations between pro-opiomelanocortin (POMC) mRNA expression in the arcuate (Arc) nucleus and (A): percentage of body weight change, (B): visceral adipose tissue, (C): neuropeptide Y (NPY) mRNA expression in the Arc, (D): glutamic acid decarboxylase (GAD65) mRNA expression in the Arc, (E): Arc NPY and GAD65 mRNA expression, (F): cannabinoid CB1 receptor (CB1R) binding density in the dorsal vagal complex (DVC) and percentage of body weight changed, (G): DVC CB1R binding density and visceral adipose tissue, and (H): DVC CB1R binding density and GAD65 mRNA expression, following 14-days olanzapine treatment or vehicle (control). Correlation analyses were made from raw data underlying the graphs presented in Figures 1 and 3. Key: <$>\raster="rg1"<$> control, ×0.5 mg/kg, ○ 0.5 mg/kg, □ 1.0 mg/kg, ▵ 2.0 mg/kg olanzapine.
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pone-0033548-g005: Correlations.Correlations between pro-opiomelanocortin (POMC) mRNA expression in the arcuate (Arc) nucleus and (A): percentage of body weight change, (B): visceral adipose tissue, (C): neuropeptide Y (NPY) mRNA expression in the Arc, (D): glutamic acid decarboxylase (GAD65) mRNA expression in the Arc, (E): Arc NPY and GAD65 mRNA expression, (F): cannabinoid CB1 receptor (CB1R) binding density in the dorsal vagal complex (DVC) and percentage of body weight changed, (G): DVC CB1R binding density and visceral adipose tissue, and (H): DVC CB1R binding density and GAD65 mRNA expression, following 14-days olanzapine treatment or vehicle (control). Correlation analyses were made from raw data underlying the graphs presented in Figures 1 and 3. Key: <$>\raster="rg1"<$> control, ×0.5 mg/kg, ○ 0.5 mg/kg, □ 1.0 mg/kg, ▵ 2.0 mg/kg olanzapine.

Mentions: POMC mRNA expression in the Arc significantly correlated to percentage body weight change (r = −0.43, p<0.05), visceral adiposity (r = −0.49, p<0.01), NPY mRNA expression (r = −0.45, p<0.05), and GAD65 mRNA expression in the Arc (r = −0.54, p<0.01) (Figure 5A–D). There was a significant positive correlation between NPY and GAD65 mRNA expression in the Arc (r = 0.69, p<0.01) (Figure 5E), however the two factors did not correlate to percentage body weight change (p>0.05). CB1R binding density in the DVC correlated to percentage body weight change (r = −0.38, p<0.05), visceral adiposity (r = −0.38, p<0.05) and GAD65 mRNA expression in the DVC (r = −0.52, p<0.01) (Figure 5F–H), and a weak correlation was observed between CB1R binding density in the Arc and percentage body weight change (r = −0.33, p = 0.08).


Alterations to melanocortinergic, GABAergic and cannabinoid neurotransmission associated with olanzapine-induced weight gain.

Weston-Green K, Huang XF, Deng C - PLoS ONE (2012)

Correlations.Correlations between pro-opiomelanocortin (POMC) mRNA expression in the arcuate (Arc) nucleus and (A): percentage of body weight change, (B): visceral adipose tissue, (C): neuropeptide Y (NPY) mRNA expression in the Arc, (D): glutamic acid decarboxylase (GAD65) mRNA expression in the Arc, (E): Arc NPY and GAD65 mRNA expression, (F): cannabinoid CB1 receptor (CB1R) binding density in the dorsal vagal complex (DVC) and percentage of body weight changed, (G): DVC CB1R binding density and visceral adipose tissue, and (H): DVC CB1R binding density and GAD65 mRNA expression, following 14-days olanzapine treatment or vehicle (control). Correlation analyses were made from raw data underlying the graphs presented in Figures 1 and 3. Key: <$>\raster="rg1"<$> control, ×0.5 mg/kg, ○ 0.5 mg/kg, □ 1.0 mg/kg, ▵ 2.0 mg/kg olanzapine.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3306411&req=5

pone-0033548-g005: Correlations.Correlations between pro-opiomelanocortin (POMC) mRNA expression in the arcuate (Arc) nucleus and (A): percentage of body weight change, (B): visceral adipose tissue, (C): neuropeptide Y (NPY) mRNA expression in the Arc, (D): glutamic acid decarboxylase (GAD65) mRNA expression in the Arc, (E): Arc NPY and GAD65 mRNA expression, (F): cannabinoid CB1 receptor (CB1R) binding density in the dorsal vagal complex (DVC) and percentage of body weight changed, (G): DVC CB1R binding density and visceral adipose tissue, and (H): DVC CB1R binding density and GAD65 mRNA expression, following 14-days olanzapine treatment or vehicle (control). Correlation analyses were made from raw data underlying the graphs presented in Figures 1 and 3. Key: <$>\raster="rg1"<$> control, ×0.5 mg/kg, ○ 0.5 mg/kg, □ 1.0 mg/kg, ▵ 2.0 mg/kg olanzapine.
Mentions: POMC mRNA expression in the Arc significantly correlated to percentage body weight change (r = −0.43, p<0.05), visceral adiposity (r = −0.49, p<0.01), NPY mRNA expression (r = −0.45, p<0.05), and GAD65 mRNA expression in the Arc (r = −0.54, p<0.01) (Figure 5A–D). There was a significant positive correlation between NPY and GAD65 mRNA expression in the Arc (r = 0.69, p<0.01) (Figure 5E), however the two factors did not correlate to percentage body weight change (p>0.05). CB1R binding density in the DVC correlated to percentage body weight change (r = −0.38, p<0.05), visceral adiposity (r = −0.38, p<0.05) and GAD65 mRNA expression in the DVC (r = −0.52, p<0.01) (Figure 5F–H), and a weak correlation was observed between CB1R binding density in the Arc and percentage body weight change (r = −0.33, p = 0.08).

Bottom Line: Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc.Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY.This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission.

View Article: PubMed Central - PubMed

Affiliation: Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, Australia.

ABSTRACT

Background/aim: Second generation antipsychotics (SGAs) are used to treat schizophrenia but can cause serious metabolic side-effects, such as obesity and diabetes. This study examined the effects of low to high doses of olanzapine on appetite/metabolic regulatory signals in the hypothalamus and brainstem to elucidate the mechanisms underlying olanzapine-induced obesity.

Methodology/results: Levels of pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and glutamic acid decarboxylase (GAD(65), enzyme for GABA synthesis) mRNA expression, and cannabinoid CB1 receptor (CB1R) binding density (using [(3)H]SR-141716A) were examined in the arcuate nucleus (Arc) and dorsal vagal complex (DVC) of female Sprague Dawley rats following 0.25, 0.5, 1.0 or 2.0 mg/kg olanzapine or vehicle (3×/day, 14-days). Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc. GAD(65) mRNA expression increased and CB1R binding density decreased in the Arc and DVC. Alterations to neurotransmission signals in the brain significantly correlated with body weight and adiposity. The minimum dosage threshold required to induce weight gain in the rat was 0.5 mg/kg olanzapine.

Conclusions: Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY. This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission. Metabolic dysfunction can be modelled in the female rat using low, clinically-comparable olanzapine doses when administered in-line with the half-life of the drug.

Show MeSH
Related in: MedlinePlus