Gene-transfer technology: a preventive neurotherapy to curb obesity, ameliorate metabolic syndrome and extend life expectancy

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Leptin insufficiency at crucial target sites in the hypothalamic circuitries that integrate energy intake and expenditure underlies abnormal rates of fat accumulation. The payload of this ‘fat burden’ is metabolic syndrome, a cluster of life-threatening metabolic afflictions, and a shorter lifespan. Currently available therapies employed to combat obesity have disadvantages such as poor compliance for lifestyle modification or transient effectiveness and undesirable side-effects of pharmacological interventions. Recent studies suggest that neurotherapy comprising a single central administration of recombinant adeno-associated virus vector encoding the leptin gene severely depletes fat and ameliorates the major symptoms of metabolic syndrome for extended periods in rodents. These persistent benefits avert the deleterious impact of the ‘fat burden’ and extend life expectancy. Thus, the novel approach of central gene-transfer technology has distinct advantages over current therapies and has the potential to correct or slow the progression of inherited or acquired hypothalamic diseases.

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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