Obesity treatment: novel peripheral targets

Field, Benjamin; Chaudhri, Owais B.; Bloom, Stephen R.

doi:10.1111/j.1365-2125.2009.03522.x

Cited by 59 publications

(52 citation statements)

References 214 publications

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“…Obese patients without this genetic disorder typically show increased leptin levels, and in these individuals leptin treatment does not result in substantial weight reduction owing to a phenomenon known as leptin resistance (32). Therefore, future clinical applications of this designer network may need to have leptin replaced by other anorectic peptides (33). Having the potential to address such a wide set of pathologies, the concept of drug-based gene therapies may improve treatment success and provide new therapies for multifactorial diseases.…”

Section: Discussionmentioning

confidence: 99%

Pharmaceutically controlled designer circuit for the treatment of the metabolic syndrome

Hamri

Zwicky

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Synthetic biology has significantly advanced the design of genetic devices that can reprogram cellular activities and provide novel treatment strategies for future gene-and cell-based therapies. However, many metabolic disorders are functionally linked while developing distinct diseases that are difficult to treat using a classic one-drug-one-disease intervention scheme. For example, hypertension, hyperglycemia, obesity, and dyslipidemia are interdependent pathologies that are collectively known as the metabolic syndrome, the prime epidemic of the 21st century. We have designed a unique therapeutic strategy in which the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin. Therefore, the signal transduction of a chimeric traceamine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements. Based on this designer signaling cascade, it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc mIgG -Leptin, a bifunctional therapeutic peptide hormone that combines the glucagon-like peptide 1 (GLP-1) and leptin via an IgG-Fc linker. In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia. Using a clinically licensed drug to coordinate expression of therapeutic transgenes combines drug-and genebased therapies for coordinated treatment of functionally related metabolic disorders. T he metabolic syndrome is a combination of disorders and risk factors including hypertension, hyperglycemia, obesity, and dyslipidemia that show an extremely complex and littleunderstood interdependent pathophysiology and collectively increase the risk for cardiovascular diseases that remain the prime cause of mortality worldwide (1-8). Currently available therapies independently target each of the individual disorders and risk factors, but a well-coordinated collective treatment strategy does not exist (2). We have therefore designed a synthetic signaling cascade in which a clinically licensed small-molecule drug finetunes expression of therapeutic transgenes. The combination of drug-and gene-based therapies enables simultaneous treatment of all key metabolic syndrome pathologies. Guanabenz (Wytensin) is a clinically licensed antihypertensive drug that is thought to activate alpha-2-selective adrenergic receptors in the central nervous system, thereby reducing the sympathetic outflow to heart, kidney, and peripheral vasculature and decreasing the systolic and diastolic blood pressure (9). Recently, guanabenz was also identified as an agonist of the trace amine-associated receptor 1 (TAAR1) (10). TAARs are G protein-coupled receptors located in the neu...

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Section: Discussionmentioning

confidence: 99%

Pharmaceutically controlled designer circuit for the treatment of the metabolic syndrome

Hamri

Zwicky

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus the ability to replicate the gut hormone profile associated with gastric bypass surgery, using pharmacological interventions could offer a promising treatment for obesity [18,19]. We describe the current understanding of systems involved in appetite regulation within the CNS and gut and illustrate their complexity and potential as therapeutic targets for obesity.…”

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confidence: 99%

The role of gut hormones and the hypothalamus in appetite regulation

et al. 2010

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Abstract. The World Health Organisation has estimated that by 2015 approximately 2.3 billion adults will be overweight and more than 700 million obese. Obesity is associated with an increased risk of diabetes, cardiovascular events, stroke and cancer. The hypothalamus is a crucial region for integrating signals from central and peripheral pathways and plays a major role in appetite regulation. In addition, there are reciprocal connections with the brainstem and higher cortical centres. In the arcuate nucleus of the hypothalamus, there are two major neuronal populations which stimulate or inhibit food intake and influence energy homeostasis. Within the brainstem, the dorsal vagal complex plays a role in the interpretation and relaying of peripheral signals. Gut hormones act peripherally to modulate digestion and absorption of nutrients. However, they also act as neurotransmitters within the central nervous system to control food intake. Peptide YY, pancreatic polypeptide, glucagon-like peptide-1 and oxyntomodulin suppress appetite, whilst ghrelin increases appetite through afferent vagal fibres to the caudal brainstem or directly to the hypothalamus. A better understanding of the role of these gut hormones may offer the opportunity to develop successful treatments for obesity. Here we review the current understanding of the role of gut hormones and the hypothalamus on food intake and body weight control.

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“…These differences have also important implications for lifestyle intervention (nutrition and exercise) and drug therapy. The dramatic increase in the prevalence of overweight and obesity, affecting more than 1.1 billion individuals worldwide, has resulted in a major burden on healthcare resources in developed countries (Field et al 2009;Hainer 2011). Excess fat mass increases the risk of mortality overall and increases individually the risk of chronic diseases like type 2 diabetes, hypertension, cardiovascular disease, stroke, osteoarthritis, obstructive sleep apnoea and certain cancers with sex-specific differences Kautzky-Willer and Handisurya 2009).…”

Section: Obesitymentioning

confidence: 96%