Endocrine, Metabolic & Immune Disorders-Drug Targets - Volume 11, Issue 3, 2011

As body weight increases, there is an increase in the risk of cardiovascular and metabolic disease at all ages. The combination of obesity, hypertension and diabetes, referred to as the metabolic syndrome, is common and causes significant morbidity and mortality throughout the world. Understanding the causes and consequences of these chronic disorders, and providing rational treatment options, may improve health and lower healthcare costs. This hot issue begins with a review by Iyer and colleagues of the marked differences between males and females in both the development and the responses to pharmacological interventions of metabolic disorders such as obesity. Since most preclinical studies on animal models of the metabolic syndrome are performed in males, they argue that a better appreciation of gender differences will allow the development of relevant gender-based therapeutic interventions for chronic obesity-related diseases. Muhlhausler & Ong continue the theme with a review on the programming of food intake and its relationship with maternal diet, especially in association with an oversupply of energy, fat and sugar. The association between the increased risk of obesity in the offspring in adulthood and maternal obesity and overnutrition is well-established. The changes induced by maternal overnutrition on the development of systems regulating appetite and food preferences, including how these systems interact to stimulate the excess consumption in the offspring that predispose to obesity, are now starting to be unravelled. Since hypertension is a key component of the metabolic syndrome, it is logical to examine the role of one of the major control mechanisms for blood pressure, the renin-angiotensin system, in the control of obesity. Mathai and co-workers discuss how angiotensin II as the major peptide hormone of this system influences important determinants of adipose tissue growth such as appetite and metabolism in adipose tissue and peripheral organs. The widespread availability of highly selective inhibitors of the renin-angiotensin system for the treatment of hypertension and heart failure may allow the definition of pleiotropic responses of these compounds on the body weight of obese patients. As the renin-angiotensin system controls blood pressure, so 5'-adenosine monophosphate-activated protein kinase (AMPK) is the cellular master-switch for control of energy homeostasis. The function of this enzyme is complex and probably involves all cells in the body, as expected for the control of energy; this complexity has been characterised in the review of Mor & Unnikrishnan. This also indicates that AMPK is a valid target for the development of new drugs and the testing of natural products for therapeutic efficacy throughout the body in the metabolic syndrome. Stearoyl-CoA desaturase catalyses the formation of monounsaturated from saturated fatty acids in the formation of the polyunsaturated fatty acids. Poudyal & Brown have evaluated the role of stearoyl-CoA desaturase as a homeostatic check-point between glucose and fatty acid metabolism in the development and progression of obesity. In obesity, stearoyl-CoA desaturase has many roles, including interacting with inflammatory responses and receptors such as the PPARs. The longer chain polyunsaturated fatty acids are present in fish oil. Abeywardena and Patten have summarised the extensive evidence for the roles of the fish oils in the different aspects of the metabolic syndrome, especially the modest reduction in blood pressure, the consistent fall in concentrations of plasma triglycerides and the improvement in endothelial function. Thus, these longchain polyunsaturated fatty acids should improve cardiometabolic health, without interacting with commonly used medications for hypertension, diabetes or obesity. Obesity is considered as a low-grade inflammatory disorder with cellular damage from the lipid inflammatory mediators. Vanden Berghe and colleagues have analyzed in molecular detail how kurarinone, a lavandulyl flavanone isolated from Sophora flavescens, suppresses nuclear factor-κB (NFκB)-driven interleukin-6 (IL6) expression and cancer cell growth. This clear demonstration of the mapping of specific molecular pathways for natural products to suppress selective inflammatory pathways may show new ways to treat metabolic syndrome and other inflammatory disorders. In summary, this hot issue provides an up-to-date account of some of the exciting areas in research particularly related to the metabolic syndrome. Both basic and clinical research will be needed to find appropriate targets for intervention in the metabolic syndrome. However, these targets are likely to be relevant in other human endocrine, metabolic and immune disorders and not unique to the metabolic syndrome.

Metabolic syndrome as a clustering of risk factors for diabetes and cardiovascular disease affects both men and women, but with important gender differences. Animal models have been used to understand disease progression and define therapeutic options, but most pre-clinical research on metabolic syndrome is undertaken in males. This opinion piece discusses the differences in male and female physiology that may influence both the development and the responses to pharmacological interventions of metabolic disorders, especially obesity. An appreciation of gender differences should improve the design and usefulness of biomedical experimental research to allow the development of relevant genderbased treatment options for chronic diseases including obesity, metabolic and cardiovascular diseases.

There is now clear evidence from population-based and experimental animal studies that maternal obesity and maternal overnutrition, particularly excessive intake of high-fat and high-sugar diets, is associated with an increased risk of obesity and type 2 diabetes in the offspring. Whilst the physiological reasons for this association are still not fully understood, one of the key pathways appears to be the ability of exposure to an oversupply of energy, fat and sugar during critical windows of development to program an increased food intake in the offspring. This review will focus on our current understanding of the programming of food intake, with a focus on the importance of the maternal diet. Specifically, we will discuss how exposure to an increased energy supply before birth and in early infancy, and/or increased maternal intake of palatable foods alters the development of the systems regulating appetite and food preferences, and how these changes interact to promote excess consumption and thus predispose the offspring to weight gain and obesity.

Obesity is associated with increased body fat composition and elevated risk of metabolic and cardiovascular disease. The activity of the renin-angiotensin system is generally increased in obesity and experimental evidence has shown that angiotensin influences appetite and metabolism as well as mechanisms that induce adipose tissue growth and metabolism in peripheral organs. This review summarises some of the key evidence from animal and human experiments that links the renin-angiotensin system to obesity and metabolic disease. This research has been greatly aided by the continuing development of new pharmaceuticals that inhibit the renin-angiotensin system. While their primary use is in the treatment of hypertension and heart failure, a range of experimental and clinical evidence indicates their potential use in the treatment of obesity and metabolic disease.

Lifestyle changes such as physical inactivity combined with calorie-rich, low-fibre diets have triggered an explosive surge in metabolic syndrome, outlined as a cluster of heart attack risk factors such as insulin resistance, raised fasting plasma glucose, abdominal obesity, high cholesterol and high blood pressure. By acting as a master-switch of energy homeostasis and associated pathophysiological phenomena, 5'-adenosine monophosphate-activated protein kinase (AMPK) appears to orchestrate the adaptive physiology of energy deficit, suggesting that the sedentary modern human could be suffering from chronic suboptimal AMPK activation. Addressing individual targets with potent ligands with high specificity may be inappropriate (it has not yielded any molecule superior to the sixty year old metformin) because this strategy cannot address a cluster of interrelated pathologies. However, spices, dietary supplements and nutraceuticals attenuate the multiple symptoms of metabolic syndrome in a collective and perhaps more holistic fashion with fewer adverse events. Natural selection could have favoured races that developed a taste for spices and dietary supplements, most of which are not only antioxidants but also activators of AMPK. The review will outline the various biochemical mechanisms and pathophysiological consequences of AMPK activation involving the cluster of symptoms that embrace metabolic syndrome and beyond. Recent advances that integrate energy homeostasis with a number of overarching metabolic pathways and physiological phenomena, including inflammatory conditions, cell growth and development, malignancy, life span, and even extending into environmental millieu, as in obesity mediated by gut microflora and others will also be outlined.

Stearoyl-CoA desaturase 1 (SCD-1) is the rate-limiting enzyme that catalyses the conversion of saturated to monounsaturated fatty acids. Increased SCD-1 expression and activity have been implicated in cancer, cardiovascular diseases, insulin resistance and obesity. Studies with humans, wild-type rodents, knock-out mice and cells in culture show that SCD-1 inhibition decreases lipogenesis and increases GLUT4-mediated glucose uptake in skeletal muscle. In this review, we will evaluate the role of SCD-1 as a homeostatic check-point between glucose and fatty acid metabolism in the development and progression of obesity. In addition to the role of SCD-1 in glucose and fatty acid metabolism, we will also discuss the expression and regulation of SCD-1, its specific interactions with inflammatory responses and PPARs, the role of SCD-1 derived MUFAs in obesity and the relevance of SCD desaturation index as a predictor of obesity and metabolic syndrome. Additionally, we will explore the prospects of SCD-1 as a potential drug target for the management of obesity and related disorders.

Cardiovascular disease is the leading cause of mortality in many economically developed nations, and its incidence is increasing at a rapid rate in emerging economies. Diet and lifestyle issues are closely associated with a myriad of cardiovascular disease risk factors including abnormal plasma lipids, hypertension, insulin resistance, diabetes and obesity, suggesting that diet-based approaches may be of benefit. Omega-3 longchain-polyunsaturated fatty acids (ω3 LC-PUFA) are increasingly being used in the prevention and management of several cardiovascular risk factors. Both the ω3 and ω6 PUFA families are considered essential, as the human body is itself unable to synthesize them. The conversion of the two precursor fatty acids - linoleic acid (18:2ω6) and α-linoleic acid (α18:3ω3) - of these two pathways to longer (≥ C20) PUFA is inefficient. Although there is an abundance of ω6 PUFA in the food supply; in many populations the relative intake of ω3 LC-PUFA is low with health authorities advocating increased consumption. Fish oil, rich in eicosapentaenoic (EPA, 20:5ω3) and docosahexaenoic (DHA, 22:6ω3) acids, has been found to cause a modest reduction in blood pressure at a dose level of >3g/d both in untreated and treated hypertensives. Whilst a multitude of mechanisms may contribute to the blood pressure lowering action of ω3 LC-PUFA, improved vascular endothelial cell function appears to play a central role. Recent studies which evaluated the potential benefits of fish oil in type-2 diabetes have helped to alleviate concerns raised in some previous studies which used relatively large dose (5-8 g/d) and reported a worsening of glycemic control. Several meta-analyses have confirmed that the most consistent action of ω3 LC-PUFA in insulin resistance and type-2 diabetes is the reduction in triglycerides. In some studies, fish oil has been found to cause a small rise in LDL-cholesterol, but a change in the LDL particle size, from the smaller more atherogenic form to the larger, less damaging particle size, have also been noted. ω3 LC-PUFA are effective modulators of the inflammation that accompanies several cardio-metabolic abnormalities. Taking into consideration the pleiotropic nature of their actions, it can be concluded that dietary supplementation with ω3 LC-PUFA will lead to improvements in cardio-metabolic health parameters. These fatty acids pose only minor side effects and more importantly, do not interact adversely with the common drug therapies used in the management and treatment of hypertension, dyslipidemia, type-2 diabetes, and obesity/ metabolic syndrome, but in some instances work synergistically, thereby providing additional cardiovascular benefits.

We have analyzed in molecular detail how kurarinone, a lavandulyl flavanone isolated from Sophora flavescens, suppresses nuclear factor-κB (NFκB)-driven interleukin-6 (IL6) expression and cancer cell growth. Interleukin-6 (IL6), involved in cancer-related inflammation, acts as an autocrine and paracrine growth factor, which promotes angiogenesis, metastasis, and subversion of immunity, and changes responsivity to hormones and to chemotherapeutics. Our results in estrogen-unresponsive fibroblasts, ribosomal S6 kinase 2 kinase (RSK2) knockout cells, and estrogen receptor (ER)-deficient breast tumor cells show that kurarinone can inhibit tumor cell proliferation and selectively block nuclear NFκB transactivation of specific target genes such as IL6, cyclin D1, SOD2 but not TNFAIP2. This occurs via attenuation of extracellular signal-regulated protein (ERK) and RSK2 kinase pathways and inhibition of S6 kinase ribosomal protein (S6RP) and histone H3 S10 phosphorylation. As constitutive NFκB and RSK2 activity are important hallmarks of human cancers, including hematopoietic malignancies and solid tumors, prenylated flavanones represent an attractive class of natural inhibitors of the ERK/RSK2 signaling pathway for cancer therapy.