Trends in Pharmacological Sciences
Gene-transfer technology: a preventive neurotherapy to curb obesity, ameliorate metabolic syndrome and extend life expectancy
Section snippets
Instinctual urge and obesity burden
Reports of the worldwide increase in the prevalence of obesity and metabolic diseases dominate the print media and airwaves (reviewed in 1, 2, 3). Accumulation of excess body fat because of increased consumption of energy-rich diets and a sedentary lifestyle result in obesity. This ‘fat burden’ increases the risks of developing metabolic syndrome and several forms of cancer and increases the risk of having a shortened life expectancy 1, 2, 3, 4, 5, 6, 7, 8. Although genetic factors predispose a
Feedback circuitry integrating energy homeostasis
The economics of treating obesity and related diseases have propelled the scientific community to study why the body's energy homeostatic control, either progressively with age or abruptly, is biased towards increased fat deposition rather than disposal of fat 3, 9, 10, 11, 12. The basic tenets of the intricate feedback communications between the circulating hormonal environment and the hypothalamus, and how each responds to novel nutritional and lifestyle challenges have been deciphered
Interventional therapies
An ideal anti-obesity therapy should produce relatively rapid weight loss, be long-lasting and safe and perturb only minimally the dynamic homeostatic interactions among physiological and neural systems (Figure 1, Figure 2). Because clinical evidence suggests that moderate weight loss can temper the severity of obesity-related diseases, a variety of interventional therapies have been tested.
Leptin gene therapy
Because of its unique non-pathogenic and non-immunogenic biology compared with other vectors, recombinant adeno-associated virus (rAAV) has been used successfully to transfer genes of interest to a wide range of tissues in humans and animals [33]. rAAV vector can be injected at any time during the lifespan of an individual because of the stability of transgene expression and its ability to transduce expression selectively in neurons when microinjected into discrete CNS sites [33]. rAAV vector,
Metabolic syndrome
A strong etiological link between increased adiposity, metabolic syndrome and certain types of cancers is well documented 3, 4, 5, 8, 9, 21, 22, 24, 35, 36, 37. Adipose tissue is an endocrine gland that secretes several proteins in addition to leptin 16, 35, 36, 37. Adiponectin, adipsion, resistin, visfatin and the cytokines, tumor necrosis factor α (TNF-α) and interleukin 6 are implicated in metabolic disorders and have an adverse effect on insulin–glucose homeostasis 16, 35, 37.
Concluding remarks
Leptin is one of the primary signals in the energy homeostatic circuitry that restrains overeating by modulating the interplay of orexigenic and anorexigenic components of the appetite-regulating network, and by increasing thermogenic energy expenditure. Leptin insufficiency in the hypothalamus, acquired through environmental causes, propels body fat accumulation and pathophysiological sequalae of the metabolic syndrome. This knowledge has been gainfully exploited in the design of preventive
Acknowledgements
The research embodied in this publication was supported by National Institute of Health, grants DK 37273 and NS 32727. We are thankful to Sandra Clark for assistance in the preparation of this manuscript.
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Neuroendocrine control of energy homeostasis: Update on new insights
2010, Progress in Brain ResearchCitation Excerpt :Expression of hunger in response to food deprivation or restriction is associated with ghrelin hypersecretion. Seemingly, ghrelin is an important physiological signal in the genesis of the daily periodic ingestive behavior (Kalra and Kalra, 2003; Kalra et al., 2003, 2005). However, a role of ghrelin in promoting obesity is less certain because ghrelin secretion is markedly reduced concomitant with hyperleptinaemia in obese rodents and humans and leptin administration suppresses ghrelin secretion (Fig. 2) (Dube et al., 2002; Kalra and Kalra, 2003; Kalra et al., 2003, 2005; Otukonyong et al., 2005a, 2005b; Ueno et al., 2004).
Disruption in the leptin-NPY link underlies the pandemic of diabetes and metabolic syndrome: New therapeutic approaches
2008, NutritionCitation Excerpt :In fact, increased leptin transgene expression in the hypothalamus suppressed the amount of insulin discharged per episode, abolished the onset of HFD-induced hyperinsulinemia that normally precedes fat accrual, and attenuated the rapid postprandial spurt in insulin secretion [17,18,20,31,38,39]. The strongest evidence in support of our proposal that central leptin normally restrains pancreatic insulin secretion was obtained in leptin mutant ob/ob mice [3,10,22,28,31,38]. In these hyperinsulinemic mice, consuming normal chow or an HFD, leptin availability selectively in the hypothalamus, without leakage to the periphery, maintained normoinsulinemia for mice's lifetime.