PLoS ONE. 2014 March;9(3):e92358.

Cinnamon extract improves insulin sensitivity in the brain and lowers liver fat in mouse models of obesity.

Tina Sartorius, Andreas Peter, Nadja Schulz, Andrea Drescher, Ina Bergheim, Jürgen Machann, Fritz Schick, Dorothea Siegel-Axel, Annette Schürmann, Cora Weigert, Hans-Ulrich Häring, Anita M. Hennige.

 

Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Member of the German Center for Diabetes Research (DZD), University of Tuebingen, Germany.
Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tuebingen, Germany.
Department of Experimental Diabetology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
Department of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller-University of Jena, Germany.
Department of Diagnostic and Interventional Radiology, Section of Experimental Radiology, University of Tuebingen, Germany.

 

Abstract

Objectives: Treatment of diabetic subjects with cinnamon demonstrated an improvement in blood glucose concentrations and insulin sensitivity but the underlying mechanisms remained unclear. This work intends to elucidate the impact of cinnamon effects on the brain by using isolated astrocytes, and an obese and diabetic mouse model.

Methods: Cinnamon components (eugenol, cinnamaldehyde) were added to astrocytes and liver cells to measure insulin signaling and glycogen synthesis. Ob/ob mice were supplemented with extract from cinnamomum zeylanicum for 6 weeks and cortical brain activity, locomotion and energy expenditure were evaluated. Insulin action was determined in brain and liver tissues.

Results: Treatment of primary astrocytes with eugenol promoted glycogen synthesis, whereas the effect of cinnamaldehyde was attenuated. In terms of brain function in vivo, cinnamon extract improved insulin sensitivity and brain activity in ob/ob mice, and the insulin-stimulated locomotor activity was improved. In addition, fasting blood glucose levels and glucose tolerance were greatly improved in ob/ob mice due to cinnamon extracts, while insulin secretion was unaltered. This corresponded with lower triglyceride and increased liver glycogen content and improved insulin action in liver tissues. In vitro, Fao cells exposed to cinnamon exhibited no change in insulin action.

Conclusions: Together, cinnamon extract improved insulin action in the brain as well as brain activity and locomotion. This specific effect may represent an important central feature of cinnamon in improving insulin action in the brain, and mediates metabolic alterations in the periphery to decrease liver fat and improve glucose homeostasis.

 

Supplementary

Insulin resistant-associated conditions such as obesity and type 2 diabetes (T2D) have reached epidemic proportions over the last three decades. A well-recognized factor for T2D is obesity, and its incidence is still rising to a worrying rate and underscores the priority for the discovery of effective therapies to combat this epidemic, particularly as overweight and obesity are the fifth leading risk for global deaths (1). A central cause of overweight and obesity is an energy imbalance between calories consumed and calories expended, and it is suggested that a complex interplay of environmental, including fetal programming, genetic, behavioral, neuronal, and endocrine factors plays a decisive role in the development of obesity and T2D.

Besides the well-established approaches to improve insulin action and secretion in patients with T2D, there is still a demand for alternative therapies. Traditional chinese medicinal plants have been used as pharmacological active compounds for a long time to treat and prevent various chronic diseases, such as diabetes. Cinnamon extracts were shown to have antidiabetic effects as several cell studies revealed an insulin-like action. The treatment of diabetic subjects with cinnamon was investigated in several clinical trials with conflicting results: in T2D patients, an improvement in blood glucose concentrations and insulin sensitivity was demonstrated (2,3), whereas other studies did not show any beneficial effect (4). However, cinnamon was never shown to affect insulin secretion in vivo (5).

The brain is the key organ to sense metabolic alterations and in turn controls food intake and glucose homeostasis, and there is great evidence that insulin is a key signal to act in the brain as it inhibits glucose production in the liver and therefore lowers blood glucose levels. The brain is involved in metabolic abnormalities seen in obesity, insulin resistance and T2D: similar to animal studies where insulin sensitivity in the brain is blunted in obese and insulin resistant mice (6), the effect of insulin on neuronal activity in humans is impaired in obesity (7) and aging (8).

Others and we identified that saturated free fatty acids cause insulin resistance in the human brain (7), and our laboratory studies in mice speak to an effect of saturated fatty acids to impair brain activity (9), locomotion and to alter sleep architecture (10). However, substances to increase or restore insulin action in the brain and improve brain activity, locomotion and favor glucose homeostasis are unknown. Of interest, cinnamon extract was described as beneficial in Alzheimer’s disease (11) and prevented cells of the cerebellum from neuronal death (12).

Stimulated by these beneficial brain effects of cinnamon, we hypothesized that alterations in insulin action in the brain might contribute to the beneficial effect of cinnamon on glucose homeostasis through the brain-liver axis.

In our study, we used extract from cinnamomum (C.) zeylanicum that is regarded to be more effective and safe compared to cinnamon related species like C. cassia, where concentrations of coumarins are extremely high and cause health risks if consumed regularly in higher quantities (13).

To substantiate our hypothesis on a brain effect of cinnamon, we first studied the in vitro effect of two major components of the essential oil obtained from the bark of cinnamomum (C.) zeylanicum: cinnamaldehyde and eugenol. We performed experiments in isolated murine astrocytes, the most abundant cell type of the brain and part of the blood-brain barrier. Astrocytes exhibit key enzymes that regulate synthesis and degradation of brain glycogen, with which neighboring neurons or axons are supplied as fuel under hypoglycemic conditions when delivery of blood glucose is insufficient to meet immediate energy requirements. The two major compounds showed altered responses on glycogen formation and insulin signaling: while eugenol significantly promoted insulin-mediated glycogen formation and benefited the insulin signaling cascade, cinnamaldehyde reduced glycogen synthesis. These results suggest that eugenol is an active component of cinnamon extract to enhance insulin signaling in the brain.

Next, we further evaluated cinnamon extract in mouse models of obesity in vivo, and used control mice weaned on a high fat diet (HFD) for 6 weeks and leptin-deficient ob/ob mice, which exhibit hyperphagia, obesity, and glucose intolerance. Cinnamon extract from cinnamomum (C.) zeylanicum was supplemented in drinking water for 6 weeks.

Figure 1_corrected

As it turns out, our hypothesis that cinnamon extract might directly modulate insulin action in the brain and exerts beneficial effects on brain activity and locomotion in vivo came true. We began studies designed to identify insulin sensitivity in the brain by using protein analysis of the insulin signaling cascade in brain tissue and radiotelemetry implants for assessing brain activity by electrocorticography (ECoG) and locomotion in conscious mice. We firstly evaluated the brain response to insulin in cinnamon extract treated ob/ob mice. Besides ameliorated insulin sensitivity in brain tissue, these mice showed increased brain activity and random and insulin-mediated locomotion, which is revealed in Figure 2. In HFD-fed control mice cinnamon extract supplementation also resulted in improved insulin sensitivity in the brain, but without any beneficial metabolic consequences.

Figure 2

Regarding the role of cinnamon extract supplementation in body energy homeostasis, we did not detect any changes in food intake, and cinnamon extract had no beneficial effect on energy expenditure and respiratory quotient in ob/ob mice. Thus, cinnamon extract did not trigger a negative energy balance by suppressing energy intake or stimulating energy expenditure. Further, despite failure of body fat mass change in ob/ob mice, cinnamon extract greatly improved glucose tolerance without any effects on insulin secretion in these heavily obese and diabetic mice (Figure 3).

Figure 3

We did not detect any changes in cholesterol and triglyceride plasma concentrations in cinnamon-treated ob/ob mice, and pro-inflammatory parameters in the plasma were not different. However, fat accumulation in the liver of ob/ob mice was affected by cinnamon supplementation: vehicle-treated ob/ob mice showed hepatic steatosis, whereas cinnamon treatment was sufficient to suppress fat accumulation in the liver substantially. We then asked the question if the energy reserves in the liver are shunted into the production of glycogen as quickly oxidizable energy source by cinnamon extract supplementation, and indeed, hepatic glycogen concentration increased by around 70% in ob/ob mice. Figure 4 shows triglyceride and glycogen concentrations in the liver of cinnamon extract-treated ob/ob mice.

Figure 4

These liver differences were interesting. To reveal if hepatic changes by cinnamon supplementation might be ascribed to the liver itself or to brain-insulin action on liver, we further performed in vitro experiments in the differentiated rat hepatoma cell line Fao and analyzed the effect of cinnamon supplementation on insulin signaling. Neither the cinnamon extract itself nor the 2 major components cinnamaldehyde and eugenol did interfere with insulin signaling.

Thus, collectively the observed phenotype demonstrated benefical effects of cinnamon extract from cinnamomum (C.) zeylanicum in the brain that translate to less liver fat content and lower blood glucose concentrations in obese and diabetic mice.

Importance of the study: our data suggest that treatment with cinnamon extract may exert important and yet unexplored effects to improve glucose homeostasis and liver fat content in obese and diabetic animals, and eugenol may represent the relevant compound to mediate this effect.

 

References:

(1)           International Diabetes Federation (2013) IDF Diabetes Atlas (6th ed.). Brussels, Belgium: International Diabetes Federation.

(2)           Davis PA, Yokoyama W (2011) Cinnamon intake lowers fasting blood glucose: meta-analysis. J Med Food 14: 884-889.

(3)           Lu T, Sheng H, Wu J, Cheng Y, Zhu J, Chen Y (2012) Cinnamon extract improves fasting blood glucose and glycosylated hemoglobin level in Chinese patients with type 2 diabetes. Nutr Res 32: 408-412.

(4)           Suppapitiporn S, Kanpaksi N, Suppapitiporn S (2006) The effect of cinnamon cassia powder in type 2 diabetes mellitus. J Med Assoc Thai 89 Suppl 3: S200-S205.

(5)           Wickenberg J, Lindstedt S, Berntorp K, Nilsson J, Hlebowicz J (2012) Ceylon cinnamon does not affect postprandial plasma glucose or insulin in subjects with impaired glucose tolerance. Br J Nutr 107: 1845-1849.

(6)           Hennige AM, Sartorius T, Lutz SZ, Tschritter O, Preissl H, Hopp S, …, Haring HU (2009) Insulin-mediated cortical activity in the slow frequency range is diminished in obese mice and promotes physical inactivity. Diabetologia 52: 2416-2424.

(7)           Tschritter O, Preissl H, Hennige AM, Stumvoll M, Porubska K, Frost R, …, Fritsche A (2006) The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: a magnetoencephalographic study. Proc Natl Acad Sci U S A 103: 12103-12108.

(8)           Tschritter O, Hennige AM, Preissl H, Grichisch Y, Kirchhoff K, Kantartzis K, …, Häring, HU (2009a) Insulin effects on beta and theta activity in the human brain are differentially affected by ageing. Diabetologia, 52, 169-171.

(9)           Tschritter O, Preissl H, Hennige AM, Sartorius T, Grichisch Y, Stefan N, …, Häring HU (2009b) The insulin effect on cerebrocortical theta activity is associated with serum concentrations of saturated nonesterified Fatty acids. J Clin Endocrinol Metab 94: 4600-4607.

(10)        Sartorius T, Ketterer C, Kullmann S, Balzer M, Rotermund C, Binder S, …, Hennige AM (2012) Monounsaturated fatty acids prevent the aversive effects of obesity on locomotion, brain activity, and sleep behavior. Diabetes 61: 1669-1679.

(11)        Frydman-Marom A, Levin A, Farfara D, Benromano T, Scherzer-Attali R, Peled S, …, Ovadia M (2011) Orally administrated cinnamon extract reduces beta-amyloid oligomerization and corrects cognitive impairment in Alzheimer’s disease animal models. PLoS One 6: e16564.

(12)        Shimada Y, Goto H, Kogure T, Kohta K, Shintani T, Itoh T, Terasawa K (2000) Extract prepared from the bark of Cinnamomum cassia Blume prevents glutamate-induced neuronal death in cultured cerebellar granule cells. Phytother Res 14: 466-468.

(13)        Lungarini S, Aureli F, Coni E (2008) Coumarin and cinnamaldehyde in cinnamon marketed in Italy: a natural chemical hazard? Food Addit Contam Part A Chem Anal Control Expo Risk Assess 25: 1297-1305.

 

Acknowledgements: This study was supported by grants from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.; 01GI0925).

 

Contact:

Tina Sartorius, Ph.D.

German Center for Diabetes Research (DZD),

Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tuebingen, D-72076 Tuebingen, Germany

Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Member of the German Center for Diabetes Research (DZD), University of Tuebingen, D-72076 Tuebingen, Germany.

tina.sartorius@med.uni-tuebingen.de

 

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