Metformin and berberine prevent olanzapine-induced weight gain in rats

Yueshan Hu, Alan J Young, Erik A Ehli, Dustin Nowotny, Paige S Davies, Elizabeth A Droke, Timothy J Soundy, Gareth E Davies, Yueshan Hu, Alan J Young, Erik A Ehli, Dustin Nowotny, Paige S Davies, Elizabeth A Droke, Timothy J Soundy, Gareth E Davies

Abstract

Olanzapine is a first line medication for the treatment of schizophrenia, but it is also one of the atypical antipsychotics carrying the highest risk of weight gain. Metformin was reported to produce significant attenuation of antipsychotic-induced weight gain in patients, while the study of preventing olanzapine-induced weight gain in an animal model is absent. Berberine, an herbal alkaloid, was shown in our previous studies to prevent fat accumulation in vitro and in vivo. Utilizing a well-replicated rat model of olanzapine-induced weight gain, here we demonstrated that two weeks of metformin or berberine treatment significantly prevented the olanzapine-induced weight gain and white fat accumulation. Neither metformin nor berberine treatment demonstrated a significant inhibition of olanzapine-increased food intake. But interestingly, a significant loss of brown adipose tissue caused by olanzapine treatment was prevented by the addition of metformin or berberine. Our gene expression analysis also demonstrated that the weight gain prevention efficacy of metformin or berberine treatment was associated with changes in the expression of multiple key genes controlling energy expenditure. This study not only demonstrates a significant preventive efficacy of metformin and berberine treatment on olanzapine-induced weight gain in rats, but also suggests a potential mechanism of action for preventing olanzapine-reduced energy expenditure.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Rat body weight gained during…
Figure 1. Rat body weight gained during treatment (vehicle, olanzapine, olanzapine + berberine, olanzapine + metformin) (A).
* denotes significant difference between olanzapine and control group at P

Figure 2. UCP-1 and β-actin protein expression…

Figure 2. UCP-1 and β-actin protein expression in each treatment group (vehicle, olanzapine, olanzapine +…

Figure 2. UCP-1 and β-actin protein expression in each treatment group (vehicle, olanzapine, olanzapine + berberine, olanzapine + metformin) (A).
Quantification of relative protein expression of UCP-1 to β-actin, when normalized with the control group (B). * denotes significant difference at P
Similar articles
Cited by
References
    1. Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, et al. (2006) Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity (Silver Spring) 14: 36–51. - PMC - PubMed
    1. Miyamoto S, Duncan GE, Marx CE, Lieberman JA (2005) Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 10: 79–104. - PubMed
    1. Jarskog LF, Miyamoto S, Lieberman JA (2007) Schizophrenia: new pathological insights and therapies. Annu Rev Med 58: 49–61. - PubMed
    1. Newcomer JW (2004) Metabolic risk during antipsychotic treatment. Clin Ther 26: 1936–1946. - PubMed
    1. Muench J, Hamer AM (2010) Adverse effects of antipsychotic medications. Am Fam Physician 81: 617–622. - PubMed
Show all 66 references
Publication types
MeSH terms
Grant support
Avera Research Institute sponsored this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 2. UCP-1 and β-actin protein expression…
Figure 2. UCP-1 and β-actin protein expression in each treatment group (vehicle, olanzapine, olanzapine + berberine, olanzapine + metformin) (A).
Quantification of relative protein expression of UCP-1 to β-actin, when normalized with the control group (B). * denotes significant difference at P

References

    1. Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, et al. (2006) Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity (Silver Spring) 14: 36–51.
    1. Miyamoto S, Duncan GE, Marx CE, Lieberman JA (2005) Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 10: 79–104.
    1. Jarskog LF, Miyamoto S, Lieberman JA (2007) Schizophrenia: new pathological insights and therapies. Annu Rev Med 58: 49–61.
    1. Newcomer JW (2004) Metabolic risk during antipsychotic treatment. Clin Ther 26: 1936–1946.
    1. Muench J, Hamer AM (2010) Adverse effects of antipsychotic medications. Am Fam Physician 81: 617–622.
    1. Citrome L, Holt RI, Walker DJ, Hoffmann VP (2011) Weight gain and changes in metabolic variables following olanzapine treatment in schizophrenia and bipolar disorder. Clin Drug Investig 31: 455–482.
    1. De Hert M, Detraux J, van Winkel R, Yu W, Correll CU (2012) Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 8: 114–126.
    1. Blouin M, Tremblay A, Jalbert ME, Venables H, Bouchard RH, et al. (2008) Adiposity and eating behaviors in patients under second generation antipsychotics. Obesity (Silver Spring) 16: 1780–1787.
    1. Gilles M, Hentschel F, Paslakis G, Glahn V, Lederbogen F, et al. (2010) Visceral and subcutaneous fat in patients treated with olanzapine: a case series. Clin Neuropharmacol 33: 248–249.
    1. Lindenmayer JP, Czobor P, Volavka J, Citrome L, Sheitman B, et al. (2003) Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics. Am J Psychiatry 160: 290–296.
    1. De Hert MA, van Winkel R, Van Eyck D, Hanssens L, Wampers M, et al. (2006) Prevalence of the metabolic syndrome in patients with schizophrenia treated with antipsychotic medication. Schizophr Res 83: 87–93.
    1. Haupt DW (2006) Differential metabolic effects of antipsychotic treatments. Eur Neuropsychopharmacol 16 Suppl 3 S149–155.
    1. Newcomer JW, Haupt DW (2006) The metabolic effects of antipsychotic medications. Can J Psychiatry 51: 480–491.
    1. Saddichha S, Manjunatha N, Ameen S, Akhtar S (2008) Metabolic syndrome in first episode schizophrenia - a randomized double-blind controlled, short-term prospective study. Schizophr Res 101: 266–272.
    1. Shirzadi AA, Ghaemi SN (2006) Side effects of atypical antipsychotics: extrapyramidal symptoms and the metabolic syndrome. Harv Rev Psychiatry 14: 152–164.
    1. Thakore JH (2004) Metabolic disturbance in first-episode schizophrenia. Br J Psychiatry Suppl 47: S76–79.
    1. Toalson P, Ahmed S, Hardy T, Kabinoff G (2004) The Metabolic Syndrome in Patients With Severe Mental Illnesses. Prim Care Companion J Clin Psychiatry 6: 152–158.
    1. Goudie AJ, Smith JA, Halford JC (2002) Characterization of olanzapine-induced weight gain in rats. J Psychopharmacol 16: 291–296.
    1. Liebig M, Gossel M, Pratt J, Black M, Haschke G, et al. (2010) Profiling of energy metabolism in olanzapine-induced weight gain in rats and its prevention by the CB1-antagonist AVE1625. Obesity (Silver Spring) 18: 1952–1958.
    1. Faulkner G, Cohn TA (2006) Pharmacologic and nonpharmacologic strategies for weight gain and metabolic disturbance in patients treated with antipsychotic medications. Can J Psychiatry 51: 502–511.
    1. Maayan L, Vakhrusheva J, Correll CU (2010) Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis. Neuropsychopharmacology 35: 1520–1530.
    1. Praharaj SK, Jana AK, Goyal N, Sinha VK (2011) Metformin for olanzapine-induced weight gain: a systematic review and meta-analysis. Br J Clin Pharmacol 71: 377–382.
    1. Wu RR, Zhao JP, Guo XF, He YQ, Fang MS, et al. (2008) Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study. Am J Psychiatry 165: 352–358.
    1. Chen CH, Chiu CC, Huang MC, Wu TH, Liu HC, et al. (2008) Metformin for metabolic dysregulation in schizophrenic patients treated with olanzapine. Prog Neuropsychopharmacol Biol Psychiatry 32: 925–931.
    1. Boyda HN, Procyshyn RM, Asiri Y, Wu C, Wang CK, et al. (2013) Antidiabetic-drug combination treatment for glucose intolerance in adult female rats treated acutely with olanzapine. Prog Neuropsychopharmacol Biol Psychiatry 48C: 170–176.
    1. Vuddanda PR, Chakraborty S, Singh S (2010) Berberine: a potential phytochemical with multispectrum therapeutic activities. Expert Opin Investig Drugs 19: 1297–1307.
    1. Hu Y, Ehli EA, Hudziak JJ, Davies GE (2012) Berberine and evodiamine influence serotonin transporter (5-HTT) expression via the 5-HTT-linked polymorphic region. Pharmacogenomics J 12: 372–378.
    1. Kulkarni SK, Dhir A (2010) Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res 24: 317–324.
    1. Hu Y, Davies GE (2010) Berberine inhibits adipogenesis in high-fat diet-induced obesity mice. Fitoterapia 81: 358–366.
    1. Zhang X, Zhao Y, Zhang M, Pang X, Xu J, et al. (2012) Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS One 7: e42529.
    1. Zhang Y, Li X, Zou D, Liu W, Yang J, et al. (2008) Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab 93: 2559–2565.
    1. Hu Y, Ehli EA, Kittelsrud J, Ronan PJ, Munger K, et al. (2012) Lipid-lowering effect of berberine in human subjects and rats. Phytomedicine 19: 861–867.
    1. Hu Y, Davies GE (2009) Berberine increases expression of GATA-2 and GATA-3 during inhibition of adipocyte differentiation. Phytomedicine 16: 864–873.
    1. Hu Y, Fahmy H, Zjawiony JK, Davies GE (2010) Inhibitory effect and transcriptional impact of berberine and evodiamine on human white preadipocyte differentiation. Fitoterapia 81: 259–268.
    1. Hu Y, Kutscher E, Davies GE (2010) Berberine inhibits SREBP-1-related clozapine and risperidone induced adipogenesis in 3T3-L1 cells. Phytother Res 24: 1831–1838.
    1. Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, et al. (2006) Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55: 2256–2264.
    1. Boyda HN, Procyshyn RM, Tse L, Hawkes E, Jin CH, et al. (2012) Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats. J Psychiatry Neurosci 37: 407–415.
    1. Wajchenberg BL (2000) Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 21: 697–738.
    1. Tschoner A, Engl J, Laimer M, Kaser S, Rettenbacher M, et al. (2007) Metabolic side effects of antipsychotic medication. Int J Clin Pract 61: 1356–1370.
    1. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, et al. (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122: 253–270.
    1. Xing LJ, Zhang L, Liu T, Hua YQ, Zheng PY, et al. (2011) Berberine reducing insulin resistance by up-regulating IRS-2 mRNA expression in nonalcoholic fatty liver disease (NAFLD) rat liver. Eur J Pharmacol 668: 467–471.
    1. Yang QH, Hu SP, Zhang YP, Xie WN, Li N, et al. (2011) Effect of berberine on expressions of uncoupling protein-2 mRNA and protein in hepatic tissue of non-alcoholic fatty liver disease in rats. Chin J Integr Med 17: 205–211.
    1. Kluge M, Schuld A, Himmerich H, Dalal M, Schacht A, et al. (2007) Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double-blind study. J Clin Psychopharmacol 27: 662–666.
    1. Case M, Treuer T, Karagianis J, Hoffmann VP (2010) The potential role of appetite in predicting weight changes during treatment with olanzapine. BMC Psychiatry 10: 72.
    1. Kreuzer P, Landgrebe M, Wittmann M, Hajak G, Schecklmann M, et al. (2012) [Hypothermia under olanzapine treatment: clinical case series and review of current literature]. Nervenarzt 83: 630–637.
    1. Kudoh A, Takase H, Takazawa T (2004) Chronic treatment with antipsychotics enhances intraoperative core hypothermia. Anesth Analg 98: : 111–115, table of contents.
    1. D'Agostino G, La Rana G, Russo R, Sasso O, Iacono A, et al. (2007) Acute intracerebroventricular administration of palmitoylethanolamide, an endogenous peroxisome proliferator-activated receptor-alpha agonist, modulates carrageenan-induced paw edema in mice. J Pharmacol Exp Ther 322: 1137–1143.
    1. Wang Y, Campbell T, Perry B, Beaurepaire C, Qin L (2011) Hypoglycemic and insulin-sensitizing effects of berberine in high-fat diet- and streptozotocin-induced diabetic rats. Metabolism 60: 298–305.
    1. Zhang M, Lv X, Li J, Meng Z, Wang Q, et al. (2012) Sodium caprate augments the hypoglycemic effect of berberine via AMPK in inhibiting hepatic gluconeogenesis. Mol Cell Endocrinol 363: 122–130.
    1. Makino T, Kato K, Mizukami H (2009) Processed aconite root prevents cold-stress-induced hypothermia and immuno-suppression in mice. Biol Pharm Bull 32: 1741–1748.
    1. Stefanidis A, Verty AN, Allen AM, Owens NC, Cowley MA, et al. (2009) The role of thermogenesis in antipsychotic drug-induced weight gain. Obesity (Silver Spring) 17: 16–24.
    1. Nedergaard J, Cannon B (2013) UCP1 mRNA does not produce heat. Biochim Biophys Acta 1831: 943–949.
    1. Schreiner A, Niehaus D, Shuriquie NA, Aadamsoo K, Korcsog P, et al. (2012) Metabolic effects of paliperidone extended release versus oral olanzapine in patients with schizophrenia: a prospective, randomized, controlled trial. J Clin Psychopharmacol 32: 449–457.
    1. Smith GC, Vickers MH, Shepherd PR (2011) Olanzapine effects on body composition, food preference, glucose metabolism and insulin sensitivity in the rat. Arch Physiol Biochem 117: 241–249.
    1. Feng S, Melkersson K (2012) Metabolic parameters and long-term antipsychotic treatment: a comparison between patients treated with clozapine or olanzapine. Neuro Endocrinol Lett 33: 493–498.
    1. Ikegami M, Ikeda H, Ishikawa Y, Ohsawa M, Ohashi T, et al... (2013) Olanzapine induces glucose intolerance through the activation of AMPK in the mouse hypothalamus. Eur J Pharmacol.
    1. Fell MJ, Anjum N, Dickinson K, Marshall KM, Peltola LM, et al. (2007) The distinct effects of subchronic antipsychotic drug treatment on macronutrient selection, body weight, adiposity, and metabolism in female rats. Psychopharmacology (Berl) 194: 221–231.
    1. Sejima E, Yamauchi A, Nishioku T, Koga M, Nakagama K, et al. (2011) A role for hypothalamic AMP-activated protein kinase in the mediation of hyperphagia and weight gain induced by chronic treatment with olanzapine in female rats. Cell Mol Neurobiol 31: 985–989.
    1. Skrede S, Ferno J, Vazquez MJ, Fjaer S, Pavlin T, et al. (2012) Olanzapine, but not aripiprazole, weight-independently elevates serum triglycerides and activates lipogenic gene expression in female rats. Int J Neuropsychopharmacol 15: 163–179.
    1. Oh JE, Cho YM, Kwak SN, Kim JH, Lee KW, et al. (2012) Inhibition of mouse brown adipocyte differentiation by second-generation antipsychotics. Exp Mol Med 44: 545–553.
    1. Russo GL, Russo M, Ungaro P (2013) AMP-activated protein kinase: a target for old drugs against diabetes and cancer. Biochem Pharmacol 86: 339–350.
    1. Lee MS, Kim IH, Kim CT, Kim Y (2011) Reduction of body weight by dietary garlic is associated with an increase in uncoupling protein mRNA expression and activation of AMP-activated protein kinase in diet-induced obese mice. J Nutr. 141: 1947–53.
    1. Martínez de Morentin PB, Whittle AJ, Fernø J, Nogueiras R, Diéguez C, et al. (2012) Nicotine induces negative energy balance through hypothalamic AMP-activated protein kinase. Diabetes 61: 807–17.
    1. Jassim G, Skrede S, Vazquez MJ, Wergedal H, Vik-Mo AO, et al. (2012) Acute effects of orexigenic antipsychotic drugs on lipid and carbohydrate metabolism in rat. Psychopharmacology (Berl) 219: 783–794.
    1. Dessalle K, Euthine V, Chanon S, Delarichaudy J, Fujii I, et al. (2012) SREBP-1 transcription factors regulate skeletal muscle cell size by controlling protein synthesis through myogenic regulatory factors. PLoS One 7: e50878.
    1. Lecomte V, Meugnier E, Euthine V, Durand C, Freyssenet D, et al. (2010) A new role for sterol regulatory element binding protein 1 transcription factors in the regulation of muscle mass and muscle cell differentiation. Mol Cell Biol 30: 1182–1198.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe