Anti-obesity potential of Clerodendron glandulosum.Coleb leaf aqueous extract

Ethnopharmacological relevance

Clerodendron glandulosum.Coleb leaf aqueous extract (CG) is traditionally used by people of North-East India to alleviate symptoms of diabetes, obesity and hypertension. Previous study from our laboratory have documented anti-diabetic and anti-hypertensive properties of CG extract but, till date there are no pharmacological studies available on its anti-obesity potential. This inventory investigates the underlining molecular mechanism/s of CG induced regulation of in vivo HFD induced obesity and in vitro adipocyte differentiation.

Aim

To evaluate effects of CG extract on (i) expression of genes regulating visceral adiposity and (ii) in vitro adipocyte differentiation and LEP release.

Materials and methods

Body weight, lee index, plasma lipids and LEP, mRNA expression of PPARγ-2, SREBP1c, FAS, CPT-1 and LEP in epididymal adipose tissue of control and experimental groups were evaluated. Also, potential of CG extract on in vitro adipocyte differentiation and LEP release was assessed.

Results

Supplementation of CG extract to HFD fed mice significantly prevented HFD induced increment in bodyweight, lee index, plasma lipids and LEP, visceral adiposity and adipocyte hypertrophy. Also, CG extract supplementation resulted in down regulation of PPARγ-2, SREBP1c, FAS and LEP expression along with up-regulation of CPT-1 in epididymal adipose tissue compared to HFD fed mice. In vitro study recorded significant anti-adipogenic effect of CG extract that resulted in decreased adipogenesis, TG accumulation, LEP release, G3PDH activity along with higher glycerol release without significantly altering viability of 3T3L1 pre-adipocytes.

Conclusions

Clerodendron glandulosum.Coleb extract prevents adipocyte differentiation and visceral adiposity by down regulation of PPARγ-2 related genes and Lep expression thus validating its traditional therapeutic use in controlling obesity.     

Fatty acid synthase gene regulation in primary hypothalamic neurons

Understanding the mechanisms that regulate feeding is critical to the development of therapeutic interventions for obesity. Many studies indicate that enzymes within fatty acid metabolic pathways may serve as targets for pharmacological tools to treat this epidemic. We, and others have previously demonstrated that C75, a fatty acid synthase (FAS) inhibitor, induced significant anorexia and weight loss by both central and peripheral mechanisms. Because the hypothalamus is important in the regulation of homeostatic processes for feeding control, we have identified pathways that alter the gene expression of FAS in primary hypothalamic neuronal cultures. Insulin, glucose and AICAR (an activator of AMP-activated protein kinase) affected changes in hypothalamic FAS mRNA, which may be regulated via the SREBP1c dependent or independent pathway.     

The imidazoline-like drug S23515 affects lipid metabolism in hepatocyte by inhibiting the oxidosqualene: lanosterol cyclase activity

Imidazoline-like drugs are centrally-acting antihypertensive agents that inhibit the activity of the sympathetic nervous system by interacting with the alpha2-adrenoreceptor and also with a non-adrenergic imidazoline binding site called the imidazoline 1 receptor. Recently, these molecules were proposed to play an additional role in cardiovascular diseases by acting on glucose and lipid metabolism. We used S23515, a potent imidazoline-like molecule acting selectively on blood pressure through the imidazoline 1 receptor, to decipher the effects of these drugs on lipid metabolism. We found that S23515 inhibited specifically and dose-dependently cholesterol synthesis in cultured rodent and primate hepatocytes. This hypocholesterolemic effect was likely due to the inhibition of the oxido:lanosterol cyclase (OSC), a rate-limiting enzyme in the cholesterol biosynthetic pathway. Partial OSC inhibition induced by S23515 led to the generation of 24(S),25-epoxycholesterol, a potent ligand for the liver X receptor (LXR). Furthermore, S23515 increased in human macrophages the expression of both ABCA1 and G1, the 2 ATP binding cassette transporters, which play a pivotal role in the reverse cholesterol transport. Thus, these results suggest that S23515, and potentially other imidazoline-like drugs, could exert hypolipidemic effects in addition to their hypotensive activities.     

Hypolipidemic Activity of Okra is Mediated Through Inhibition of Lipogenesis and Upregulation of Cholesterol Degradation

Little is known about the hypolipidemic activity of okra; therefore, we investigated the hypolipidemic activity of okra and its interaction with gene expression of several key components involved in lipid homeostasis. Male C57BL/6 mice were randomly divided into three groups and fed with hyperlipidemic diet or two hyperlipidemic diets supplemented with 1% or 2% okra powder for eight weeks. Results demonstrated that okra dose‐dependently decreased serum and hepatic total cholesterol and triglyceride, and enhanced fecal excretion of bile acids. Gene expression analysis revealed that okra upregulated cholesterol 7α‐hydroxylase (CYP7A1) expression, downregulated expression of sterol regulatory element‐binding protein 1c (SREBP1c) and fatty acid synthase (FAS), with no effect on sterol regulatory element‐binding protein 2 (SREBP2), 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGR), low‐density lipoprotein receptor (LDLR) and carnitine palmitoyltransferase‐1A (CPT1A). It was suggested that hypolipidemic activity of okra was mediated most likely by upregulation of cholesterol degradation through CYP7A1 and by inhibition of lipogenesis through SREBP1c and FAS. Okra raw and fractionated polysaccharide showed strong bile acid binding capacity in vitro, which may contribute to the hypolipidemic activity observed. In conclusion, okra has potential application in the management of hyperlipidemia and its associated metabolic disorders. Copyright © 2013 John Wiley & Sons, Ltd.