Leptin gene transfer in the hypothalamus enhances longevity in adult monogenic mutant mice in the absence of circulating leptin

Boghossian, Stéphane; Ueno, Naohiko; Dube, Michael G.; Kalra, Pushpa S.; Kalra, Satya P.

doi:10.1016/j.neurobiolaging.2006.08.010

Cited by 38 publications

(89 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This increased energy intake response coalesces into various pathophysiological afflictions that negatively impact the quality of daily life and longevity, namely obesity and the metabolic syndrome cluster of disorders including glucose intolerance, hyperinsulinemia, artherosclerosis, cardiovascular ailments and fatty liver, and disruption in reproduction, fluid homeostasis, temperature control and energy expenditure (12,15,35,(37)(38)(39)42).…”

Section: Functional Neuroanatomy Of Hypothalamic Npymentioning

confidence: 99%

“…In addition to a pivotal role in hypothalamic integration of energy homeostasis, the hypothalamic NPY network has since been shown to play a role in neuroendocrine control of reproduction and lactation, fluid balance, growth, stress, temperature, general body metabolism and bone health (1,12,15,31,41,45,46,48,62). It is now obvious that disruption in any one or more loci in the hypothalamic network of NPY and cohorts inflicted by environmental or genetic factors leads to several metabolic and neuroendocrine diseases that adversely affect the quality of life and life span (1,4,(24)(25)(26)30,32,47).…”

Section: Introductionmentioning

confidence: 99%

“…It is now obvious that disruption in any one or more loci in the hypothalamic network of NPY and cohorts inflicted by environmental or genetic factors leads to several metabolic and neuroendocrine diseases that adversely affect the quality of life and life span (1,4,(24)(25)(26)30,32,47). The focus of this review is to summarize our recent efforts to characterize the potential health benefit of experimentally imposed lifetime restraint on hypothalamic NPYergic signaling by leptin, the endogenous adipocyte hormone that is intimately involved in the hypothalamic integration of energy and neuroendocrine homeostasis (2,3,9,10,(12)(13)(14)(15)(19)(20)(21)23,33,37,38,42,48,60,61).…”

Section: Introductionmentioning

confidence: 99%

“…Several metabolic and endocrine biomarkers of aging were absent after a single icv injection of rAAVlep in leptin deficient ob/ob mice, including glucose intolerance, hyperinsulinemia, dyslipidemia and diminution in circulating levels of ghrelin and insulin-like growth factor-1, and altered secretion of proinflammatory cytokines and adipokines (2,10,12,15,37,53,60,61). Repression of these deleterious metabolic biomarkers of aging, in aggregate, seemed to reduce mortality and double the lifespan of these mice (15,37).…”

mentioning

confidence: 99%

“…Leptin gene therapy increased testis weight, improved bone health, and suppressed fatty liver. Conceivably, these benefits were a consequence of blockade of leptin insufficiency-induced disintegration of the hypothalamic control on various physiological and neuroendocrine functions (12,15,37).…”

mentioning

confidence: 99%

See 4 more Smart Citations

To subjugate NPY is to improve the quality of life and live longer

Kalra

2007

Peptides

View full text Add to dashboard Cite

The interactive network of Neuropeptide Y (NPY) and cohorts is necessary for integrating the hypothalamic regulation of appetite and energy expenditure with the endocrine and neuroendocrine systems on a daily basis. Genetic and environmental factors that produce an insufficiency of leptin restraint on NPY and cognate receptors deregulate the homeostasis to engender various lifethreatening risk factors. Recent studies from our laboratory show that neurotherapy consisting of a single central administration of recombinant adeno-associated virus vector encoding the leptin gene can repress the hypothalamic NPY system for the lifetime of rodents. A major benefit of this stable tonic restraint is deceleration of pathophysiologic sequalae that shorten life span. These include suppression of weight gain, fat accumulation, circulating adipokines, amelioration of major symptoms of metabolic syndrome, improved reproduction and bone health. Thus, sustained repression of NPY signaling in the hypothalamus by leptin transgene expression can improve the quality of life and extend longevity.

show abstract

Section: Functional Neuroanatomy Of Hypothalamic Npymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

To subjugate NPY is to improve the quality of life and live longer

Kalra

2007

Peptides

View full text Add to dashboard Cite

show abstract

Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats

Iwaniec

Boghossian

Trevisiol

et al. 2011

Journal of Bone and Mineral Research

Self Cite

View full text Add to dashboard Cite

Hypothalamic leptin gene therapy normalizes the mosaic skeletal phenotype of leptin-deficient ob/ob mice. However, it is not clear whether increased hypothalamic leptin alters bone metabolism in animals already producing the hormone. The objective of this study was to evaluate the long duration effects of recombinant adeno-associated virus-rat leptin (rAAV-Lep) hypothalamic gene therapy on weight gain and bone metabolism in growing and skeletally mature leptin-replete female Sprague-Dawley rats. Rats were either unoperated or implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either rAAV-Lep or rAAV-GFP (control vector encoding green fluorescent protein) and maintained on standard rat chow fed ad lib for either 5 or 10 weeks (starting at 3 months of age) or 18 weeks (starting at 9 months of age). Tibiae, femora, or lumbar vertebrae were analyzed by microcomputed tomography and/or histomorphometry. In comparison to age-matched rAAV-GFP rats, rAAV-Lep rats maintained a lower body weight for the duration of studies. At 5 weeks post-vector administration, rAAV-Lep rats had lower cancellous bone volume and bone marrow adiposity but higher osteoblast perimeter compared to non-operated controls. However, these values did not differ between the two groups at 10 weeks post-vector administration. Differences in cancellous bone volume and architecture were not detected between the rAAV-Lep and rAAV-GFP groups at either time point. Also, rAAV-Lep had no negative effects on bone in the 9-month old skeletally mature rats at 18 weeks post-vector administration. We hypothesize that the transient reductions in bone mass and bone marrow adiposity at 5 weeks post-vector administration were due to hypothalamic surgery. We conclude that increased hypothalamic leptin, sufficient to prevent weight gain, has minimal specific effects (rAAV-Lep versus rAAV-GFP) on bone metabolism in normal female rats.

show abstract

Leptin Therapy as a Substitute for Insulin Replacement in Experimental Models of Diabetes: Clinical Implications in Humans

Kalra

2014

Leptin

View full text Add to dashboard Cite

Leptin gene transfer in the hypothalamus enhances longevity in adult monogenic mutant mice in the absence of circulating leptin

Cited by 38 publications

References 58 publications

To subjugate NPY is to improve the quality of life and live longer

To subjugate NPY is to improve the quality of life and live longer

Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats

Leptin Therapy as a Substitute for Insulin Replacement in Experimental Models of Diabetes: Clinical Implications in Humans

Contact Info

Product

Resources

About