Transgenic Complementation of Leptin-Receptor Deficiency

Kowalski, Timothy J.; Liu, Shun Mei; Leibel, Rudolph L.; Chua, Streamson C.

doi:10.2337/diabetes.50.2.425

Cited by 137 publications

(105 citation statements)

References 67 publications

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“…However, the brain is also felt to be involved in leptin regulation. Transgenic complementation of leptin receptor in mice with homozygous leptin receptor deficiency partially rescued the effects of leptin deficiency in these mice, and resulted in increased expression of regulating hypothalamic genes (33). Thus both central nervous system and direct peripheral actions of leptin are thought to be involved in the regulation of leptin secretion.…”

Section: Discussionmentioning

confidence: 97%

Leptin Levels among Prepubertal Children with Down Syndrome Compared with Their Siblings

Magge

O'Neill

Shults

et al. 2008

The Journal of Pediatrics

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Objectives-To compare levels of leptin and other obesity-related hormones between prepubertal children with Down syndrome (DS), a population at high obesity risk, and unaffected siblings, to better understand the pathophysiology of obesity in children with DS.Study design-Cross-sectional study of 35 children with DS and 33 control siblings, ages 4 to 10 years, with a fasting blood sample, and anthropometric measurements to estimate body composition. Generalized estimating equations were used to account for the lack of independence between siblings.Results-In addition to having higher body mass index (BMI) and percent body fat, children with DS had higher leptin levels than unaffected siblings, even after adjustment for age, sex, race, and ethnicity (difference: 5.8 ng/ml, 95% CI: 2.4-9.3, p=0.001), and further adjustment for percent body fat (difference: 2.7 ng/ml, 95% CI: 0.08-5.4, p=0.04). Leptin and percent body fat were positively associated in both groups (p<0.0001), but with a significantly greater positive association in the DS group, suggesting a significant effect modification (p<0.0001).Conclusions-This group of children with DS had increased leptin for percent body fat than their unaffected siblings. This difference may contribute to the increased risk for obesity in children with DS. KeywordsObesity; Body Mass Index; Pediatrics; Body composition; Adiposity Individuals with Down syndrome (DS) are at increased risk for several endocrinologic conditions, including hypothyroidism, growth retardation, diabetes mellitus, and obesity (3, 4). The reason for the increased risk of obesity in this population is unclear, but several mechanisms have been suggested, including a decreased resting metabolic rate (5,6) and

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Section: Discussionmentioning

confidence: 97%

Leptin Levels among Prepubertal Children with Down Syndrome Compared with Their Siblings

Magge

O'Neill

Shults

et al. 2008

The Journal of Pediatrics

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“…Recent studies have found that neuronal deletion of leptin receptors did not result in the body weight gain achieved by the ob/ob and db/db mice (14) and that central overexpression of OB-Rb in db/db mice only partially corrected the obesity phenotype (13). These studies led us to speculate that the peripheral effects of leptin, such as in WAT, may also help regulate body weight.…”

Section: Discussionmentioning

confidence: 97%

“…Recent evidence at the cellular level further demonstrates that leptin can directly modulate glycerol release, insulin signaling, and gene expression in primary rodent adipocytes (11,12). At a genetic level, Kowalski et al (13) found that transgenic expression of the long form leptin receptor, OB-Rb, in the central nervous system could only partially correct the obesity and diabetic phenotypes of db/db mice. Cohen et al (14) demonstrated that mutant mice with brain-specific deletion of the leptin receptors developed obesity, whereas mutant mice with liver-specific deletion of leptin receptors did not exhibit any weight-related phenotype.…”

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confidence: 99%

Adipocyte-selective Reduction of the Leptin Receptors Induced by Antisense RNA Leads to Increased Adiposity, Dyslipidemia, and Insulin Resistance

Huan

Han

et al. 2003

Journal of Biological Chemistry

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Although recent evidence suggests that leptin can directly regulate a wide spectrum of peripheral functions, including fat metabolism, genetic examples are still needed to illustrate the physiological significance of direct actions of leptin in a given peripheral tissue. To this end, we used a technical knock-out approach to reduce the expression of leptin receptors specifically in white adipose tissue. The evaluation of leptin receptor reduction in adipocytes was based on real time PCR analysis of the mRNA levels, Western blot analysis of the proteins, and biochemical analysis of leptin signaling capability. Despite a normal level of leptin receptors in the hypothalamus and normal food intake, mutant mice developed increased adiposity, decreased body temperature, hyperinsulinemia, hypertriglyceridemia, impaired glucose tolerance and insulin sensitivity, as well as elevated hepatic and skeletal muscle triglyceride levels. In addition, a variety of genes involved in regulating fat and glucose metabolism were dysregulated in white adipose tissue. These include tumor necrosis factor-␣, adiponectin, leptin, fatty acid synthase, sterol regulatory element-binding protein 1, glycerol kinase, and ␤ 3 -adrenergic receptor. Furthermore, the mutant mice are significantly more sensitive to high fat feeding with regard to developing obesity and severe insulin resistance. Thus, we provide a genetic model demonstrating the physiological importance of a peripheral effect of leptin in vivo. Importantly, this suggests the possibility that leptin resistance at the adipocyte level might be a molecular link between obesity and type 2 diabetes.

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“…The effects of leptin on the ARC appear to be important for controlling energy balance but provide only a partial explanation of the role of leptin in body weight regulation because rescue of the LR specifically in the ARC of db/db mice only partially reverses hyperphagia (26). Also, mice lacking leptin signaling specifically in pro-opiomelanocortin (POMC) neurons are only mildly obese (27).…”

Section: Multiple Cns Sites For Leptin-mediated Effects On Energy Balmentioning

confidence: 99%

Obesity-induced Hypertension: Role of Sympathetic Nervous System, Leptin, and Melanocortins

Hall

Silva

Carmo

et al. 2010

Journal of Biological Chemistry

437

400

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Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors.The worldwide prevalence of obesity and associated cardiometabolic diseases have increased dramatically in the past 2-3 decades, rapidly becoming major challenges to the health care systems of most industrialized countries. Current estimates indicate that Ͼ1 billion people in the world are overweight or obese (1). In the United States, at least 65% of adults are overweight, and approximately one-third of adults are obese with a body mass index (defined as kilograms of weight/m 2 of height) of Ͼ30 (2). In children, the prevalence of obesity has also risen rapidly in parallel with increasing obesity in adults; a recent report indicates that 18.4% of 4-year-old children in the United States are obese, with significantly higher rates of obesity in Hispanic, black, and Native American children (3).Associated with obesity is a cascade of metabolic and cardiovascular disorders, including hypertension, a primary mediator of obesity-induced cardiovascular disease. Population studies show that excess weight gain predicts future development of hypertension, and the relationship between body mass index and blood pressure (BP) 2 appears to be nearly linear in diverse populations throughout the world (4). Some studies suggest that excess weight gain may account for 65-75% of human essential hypertension (5). Moreover, clinical studies indicate that weight loss is effective in primary prevention of hypertension and in reducing BP in most hypertensive subjects (6).Although the importance of obesity as a major cause of essential hypertension is well established, the physiological and molecular mechanisms that mediate the BP effects of excess weight gain are only beginning to be elucidated. Excess Weight Gain Increases Renal SodiumReabsorption and Impairs Pressure Natriuresis Table 1 summarizes some of the changes in cardiovascular, neurohormonal, and renal function that occur in obese humans and experimental animals (4,7,8). Notable changes, in addition to increased BP, include increases in cardiac output and heart rate as well as activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS). Rapid weight gain also stimulates renal tubular sodium reabsorption, and obese subjects require higher than normal BP to maintain balance between intake and renal excretion of sodium, indicating impaired renal pressure natriuresis (4).Three factors are especially important in increasing re...

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Transgenic Complementation of Leptin-Receptor Deficiency

Abstract: Mice homozygous for the

Cited by 137 publications

References 67 publications

Leptin Levels among Prepubertal Children with Down Syndrome Compared with Their Siblings

Leptin Levels among Prepubertal Children with Down Syndrome Compared with Their Siblings

Adipocyte-selective Reduction of the Leptin Receptors Induced by Antisense RNA Leads to Increased Adiposity, Dyslipidemia, and Insulin Resistance

Obesity-induced Hypertension: Role of Sympathetic Nervous System, Leptin, and Melanocortins

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