Hypothalamic clamp on insulin release by leptin-transgene expression

Boghossian, Stéphane; Dube, Michael G.; Torto, Rita; Kalra, Pushpa S.; Kalra, Satya P.

doi:10.1016/j.peptides.2006.07.022

Cited by 39 publications

(115 citation statements)

References 53 publications

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“…This enhanced availability of bioactive leptin selectively in the hypothalamus conferred the anticipated responses from the leptin receptor expressing orexigenic and anorexigenic neuronal targets. NPY mRNA expression was suppressed and POMC mRNA expression in the ARC was simultaneously augmented (2,9,10,12,(19)(20)(21). However, quite unexpectedly, icv rAAV-lep injection failed to modify AgRP mRNA expression in NPY coexpressing neurons.…”

Section: Repression Of Hypothalamic Npy By Central Leptin-gene Therapymentioning

confidence: 91%

“…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%

“…A clamp both on post-prandial and basal rhythmic insulin secretion, either alone or in combination with reduced fat mass, seems to confer insulin hypersensitivity in these rodents (12,60,61).…”

mentioning

confidence: 96%

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

Kalra

2007

Peptides

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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.

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Section: Repression Of Hypothalamic Npy By Central Leptin-gene Therapymentioning

confidence: 91%

Section: Functional Neuroanatomy Of Hypothalamic Npymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 96%

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

Kalra

2007

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Peripheral leptin regulates bone formation

Turner

Kalra

Wong

et al. 2012

Journal of Bone and Mineral Research

228

247

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Substantial evidence does not support the prevailing view that leptin, acting through a hypothalamic relay, decreases bone accrual by inhibiting bone formation. To clarify the mechanisms underlying regulation of bone architecture by leptin, we evaluated bone growth and turnover in wild type (WT) mice, leptin receptor-deficient db/db mice, leptin-deficient ob/ob mice and ob/ob mice treated with leptin. We also performed hypothalamic leptin gene therapy to determine the effect of elevated hypothalamic leptin levels on osteoblasts. Finally, to determine the effects of loss of peripheral leptin signaling on bone formation and energy metabolism, we used bone marrow (BM) from WT or db/db donor mice to reconstitute the hematopoietic and mesenchymal stem cell compartments in lethally irradiated WT recipient mice. Decreases in bone growth, osteoblast-lined bone perimeter and bone formation rate were observed in ob/ob mice and greatly increased in ob/ob mice following subcutaneous administration of leptin. Similarly, hypothalamic leptin gene therapy increased osteoblast-lined bone perimeter in ob/ob mice. In spite of normal osteoclast-lined bone perimeter, db/db mice exhibited a mild but generalized osteopetrotic-like (calcified cartilage encased by bone) skeletal phenotype and greatly reduced serum markers of bone turnover. Tracking studies and histology revealed quantitative replacement of BM cells following BM transplantation. WT mice engrafted with db/db BM did not differ in energy homeostasis from untreated WT mice or WT mice engrafted with WT BM. Bone formation in WT mice engrafted with WT BM did not differ from WT mice, whereas bone formation in WT mice engrafted with db/db cells did not differ from the low rates observed in untreated db/db mice. In summary, our results indicate that leptin, acting primarily through peripheral pathways, increases osteoblast number and activity.

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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

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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.

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Hypothalamic clamp on insulin release by leptin-transgene expression

Cited by 39 publications

References 53 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

Peripheral leptin regulates bone formation

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

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