Recombinant Leptin for Weight Loss in Obese and Lean Adults

Heymsfield, Steven B.; Greenberg, Andrew S.; Fujioka, Ken; Dixon, Russell M.; Kushner, Robert F.; Hunt, Thomas L.; Lubina, John; Patane, Janet; Self, Barbara; Hunt, Pam; McCamish, Mark

doi:10.1001/jama.282.16.1568

Cited by 1,295 publications

(807 citation statements)

References 29 publications

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“…These results were further supported by findings from the same investigators that infusion of PYY 3-36 decreased caloric intake in both obese and lean humans by 26 and 33%, respectively, over 24 h [3]. In contrast, since most obese humans are resistant to the adipocyte-secreted hormone leptin [12], which also acts on hypothalamic neurons (including neuropeptide Y neurons) to decrease food intake, exogenous leptin administration in obese subjects had only modest success in inducing weight loss [13].…”

Section: Discussionsupporting

confidence: 52%

Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin

et al. 2005

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Aims/hypothesis: Peptide YY (PYY) is a gutderived hormone that has been shown to reduce short-term food intake in animals and humans. It has been proposed that deficiency of PYY contributes to obesity in humans. However, the physiology of PYY regulation by factors such as caloric restriction, or by other molecules important in energy homeostasis, e.g. leptin, remains to be fully elucidated. Materials and methods: We evaluated the effect on PYY levels of: (1) caloric ingestion (a mixed meal) in five healthy normal-weight subjects; (2) fasting for 2 or 3 days in eight lean men and seven lean women respectively; and (3) recombinant human leptin administration at physiological replacement and pharmacological doses. Results: PYY levels increased 50% after a mixed meal (p=0.01), and shortterm complete fasting for 2 or 3 days decreased leptin and PYY levels to 20-30% and 40-60% of baseline, respectively (both p<0.05). However, recombinant human leptin administration at physiological doses to restore the fasting-induced decrease of leptin levels and at pharmacological doses over the short term had no effect on PYY levels. Conclusions/interpretation: PYY increases after meal ingestion and decreases after fasting in a manner consistent with a meal-related signal of energy homeostasis. Importantly, circulating levels of this gut-secreted molecule are independent of regulation by leptin over the short term. These findings contribute towards our understanding of the homeostatic systems that regulate appetite in humans, including the possible redundancy of gastrointestinally secreted and adipocyte-secreted signals. This may be of importance for the future development of medications to treat obesity.

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Section: Discussionsupporting

confidence: 52%

Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin

et al. 2005

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“…In our clinical research on leptin-replacement therapy in patients with generalised lipodystrophy, the peak plasma leptin levels of the 400% dose under the protocol of once-daily injections was 34.5± 2.1 (mean±SE) ng/ml, and the therapy was well tolerated without any adverse effects for about 5 years [15]. In addition, higher leptin levels were obtained in the obese human clinical trial [33]. Therefore, the leptin levels achieved with the dose used in the present study could be clinically applied in humans.…”

Section: Discussionmentioning

confidence: 81%

“…In general, in human obesity and rodent models of diet-induced obesity, even though leptin levels rise proportionally with adiposity, the increased leptin fails to suppress the progression of obesity. Moreover, obese humans and rodents are weakly responsive to exogenously administered leptin in terms of body weight reduction [33,34]. This leptin ineffectiveness is called leptin resistance.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet

et al. 2009

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Aims/hypothesisWe have previously demonstrated the therapeutic usefulness of leptin in lipoatrophic diabetes and insulin-deficient diabetes in mouse models and could also demonstrate its dramatic effects on lipoatrophic diabetes in humans. The aim of the present study was to explore the therapeutic usefulness of leptin in a mouse model of type 2 diabetes with increased adiposity. Methods To generate a mouse model mimicking human type 2 diabetes with increased adiposity, we used a combination of low-dose streptozotocin (STZ, 120 μg/g body weight) and high-fat diet (HFD, 45% of energy as fat). Recombinant mouse leptin was infused chronically (20 ng [g body weight] −1 h −1 ) for 14 days using a mini-osmotic pump. The effects of leptin on food intake, body weight, metabolic variables, tissue triacylglycerol content and AMP-activated protein kinase (AMPK) activity were examined. Results Low-dose STZ injection led to a substantial reduction of plasma insulin levels and hyperglycaemia. Subsequent HFD feeding increased adiposity and induced insulin resistance and further augmentation of hyperglycaemia. In this model mouse mimicking human type 2 diabetes (STZ/HFD), continuous leptin infusion reduced food intake and body weight and improved glucose and lipid metabolism with enhancement of insulin sensitivity. Leptin also decreased liver and skeletal muscle triacylglycerol content accompanied by an increase of α2 AMPK activity in skeletal muscle. Pairfeeding experiments demonstrated that leptin improved glucose and lipid metabolism independently of the food intake reduction. Conclusions/interpretation This study demonstrates the beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity, indicating the possible clinical usefulness of leptin as a new glucose-lowering drug in humans.

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“…The high leptin levels associated with obesity are thought to be caused by leptin resistance, much as type 2 diabetic patients are resistant to insulin. Indeed, leptin treatment is ineffective on inhibiting food intake and increasing energy expenditure in obese people, whereas administration of leptin in people with normal weight leads to reduction in adipose tissue and weight loss [31]. It is well documented that leptin resistance is caused by defects in the leptin signaling pathway possibly at several levels, including impaired transport of leptin across the blood-brain-barrier, reduced function of the leptin receptor and defects in leptin signal transduction [32].…”

Section: Human Studiesmentioning

confidence: 99%

The leptin hypothesis of depression: a potential link between mood disorders and obesity?

Lü

2007

Current Opinion in Pharmacology

249

193

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SummaryThe adipose-derived hormone leptin is well known for its function in the control of energy homeostasis. Recent studies suggest a novel role for this adipokine in the regulation of mood and emotion. Low levels of leptin have been found to be associated with depressive behaviors in rodents and humans. Pharmacological studies indicate that leptin has antidepressant-like efficacy. Both leptin insufficiency and leptin resistance may contribute to alterations of affective status. Identifying the key brain regions that mediate leptin's antidepressant activity and dissecting its intracellular signal transduction pathways may provide new insights into the pathogenesis of depression and facilitate the development of novel therapeutic strategies for the treatment of this illness.

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Recombinant Leptin for Weight Loss in Obese and Lean Adults

Cited by 1,295 publications

References 29 publications

Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin

Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin

Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet

The leptin hypothesis of depression: a potential link between mood disorders and obesity?

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