Obesity due to high fat diet decreases the sympathetic nervous and cardiovascular responses to intracerebroventricular leptin in rats

Lu, Huiqing; Duanmu, Zhengbo; Houck, C. Riley; Jen, K.‐L. Catherine; Buison, Anne; Dunbar, Joseph C.

doi:10.1016/s0361-9230(98)00086-0

Cited by 46 publications

(41 citation statements)

References 31 publications

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“…We postulate that BP elevation in transgenic skinny mice is also due primarily to the central effect of leptin. This notion is consistent with previous reports that a single intracerebrovascular injection of leptin can increase BP in rats (40,41). The discussion, however, does not rule out the possibility that leptin can increase BP via peripheral mechanisms, because leptin receptor is expressed in peripheral tissues including vascular endothelial cells and adrenal medulla (42)(43)(44).…”

Section: Discussionsupporting

confidence: 89%

Pathophysiological role of leptin in obesity-related hypertension

Aizawa-Abe¹,

Ogawa²,

Masuzaki³

et al. 2000

J. Clin. Invest.

434

312

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IntroductionObesity is defined as increased mass of adipose tissue and confers a higher risk of arterial blood pressure (BP) elevation or hypertension (1-4). On the other hand, weight reduction lowers BP in obese hypertensive subjects (5-8), suggesting an important association between energy homeostasis and BP. However, the mechanism for that association is poorly understood. Obesity-related hypertension may be secondary to insulin resistance and/or hyperinsulinemia (2,3,8). Several lines of evidence have also suggested that increased sympathetic nerve activity may contribute to the development of obesity-related hypertension (2, 6, 7).The adipose tissue participates in the regulation of a variety of homeostatic processes as an endocrine organ that secretes many biologically active molecules such as FFA, adipsin, angiotensinogen,. Leptin is such an adipocyte-derived hormone that is involved in the regulation of food intake and body weight (10). It also increases the overall sympathetic nerve activity, which leads to a significant increase in energy expenditure (11-15). The biologic actions of leptin are thought to be mediated through the activation of leptin receptor that is expressed in the hypothalamus (16)(17)(18)(19). We and others demonstrated that the hypothalamic arcuate nucleus is a primary site of the satiety effect of leptin (20,21) and that its satiety effect is mediated at least partly by hypothalamic melanocortin system (22,23).Numerous studies have demonstrated that plasma leptin concentrations are elevated significantly in several models of rodent obesity and in human obesity in proportion to the degree of adiposity (24-26), suggesting the state of "leptin resistance" in obesity. Nevertheless, because of the potent pleiotropic actions of leptin, it is conceivable, though paradoxically, that hyperleptinemia may be involved in the pathogenesis of obesity and its related disorders. In this regard, a recent study reported a significant correlation between BP and plasma leptin concentrations in patients with essential hypertension (27), suggesting that leptin may play roles in the pathogenesis of obesity-related hypertension.We have recently produced transgenic skinny mice overexpressing leptin under the control of the liver-specific promoter and demonstrated that chronic hyperleptinemia results in complete disappearance of adipose tissue for a long period (28). These mice also exhibit increased glucose metabolism and insulin sensitivity, accompanied by an activation of insulin signaling in the skeletal muscle and liver (28,29). Accordingly, transgenic skinny mice will serve as the unique experimental model system with which to assess the long-term effects of leptin in vivo. To explore the pathophysiological role of leptin in obesity-related hypertension, we examined cardiovascular phenotypes of transgenic skinny mice whose elevated plasma leptin concentrations are comparable to those seen in obese subjects. We also studied genetically obese KKA y mice with hyperleptinemia, in which hypothalamic melano...

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Section: Discussionsupporting

confidence: 89%

Pathophysiological role of leptin in obesity-related hypertension

Aizawa-Abe¹,

Ogawa²,

Masuzaki³

et al. 2000

J. Clin. Invest.

434

312

View full text Add to dashboard Cite

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“…This rapid adaptation to increased energy availability may be designed to curtail the leptin system in order to facilitate storage of nutrients into lipid stores (1,3,(23)(24)(25). This may be accomplished by restraining leptin biosynthesis (23-25) and/or by inducing leptin resistance (1,(3)(4)(5)(6)24,26). These mechanisms would be particularly well developed in individuals or animals predisposed to weight gain and diabetes (1,11,24,25,27).…”

mentioning

confidence: 99%

“…yperphagia and elevated levels of both insulin and leptin are common features of obesity (1)(2)(3)(4)(5)(6)(7)(8). This is paradoxical because leptin is a potent inhibitor of feeding (9 -15) and is expected to decrease insulin levels via improved insulin action (16 -21) and inhibition of insulin secretion (22).…”

mentioning

confidence: 99%

Overfeeding Rapidly Induces Leptin and Insulin Resistance

et al. 2001

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In common forms of obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia coexist. Here, we demonstrate rapid induction of insulin and leptin resistance by short-term overfeeding. After 3 and 7 days on the assigned diet regimen, rats were tested for their biological responses to acute elevations in plasma insulin and leptin concentrations. Severe resistance to the metabolic effects of both leptin and insulin ensued after just 3 days of overfeeding. During the insulin clamp studies, glucose production was decreased by ϳ70% in control rats and 28 -53% in overfed rats. Similarly, leptin infusion doubled the contribution of gluconeogenesis to glucose output in control rats but failed to modify gluconeogenesis in overfed animals. These findings demonstrate a paradoxical and rapid collapse of the leptin system in response to nutrient excess. This partial failure is tightly coupled with the onset of insulin resistance. Diabetes 50:2786 -2791, 2001 H yperphagia and elevated levels of both insulin and leptin are common features of obesity (1)(2)(3)(4)(5)(6)(7)(8). This is paradoxical because leptin is a potent inhibitor of feeding (9 -15) and is expected to decrease insulin levels via improved insulin action (16 -21) and inhibition of insulin secretion (22). To reconcile these findings, it has been proposed that obesity is associated with resistance to the biological effects of both insulin and leptin (1-8). However, although it is generally assumed that leptin resistance contributes to hyperphagia (1,4,6,7), it is also possible that hyperphagia may induce leptin resistance and other metabolic sequelae of obesity. This rapid adaptation to increased energy availability may be designed to curtail the leptin system in order to facilitate storage of nutrients into lipid stores (1,3,(23)(24)(25). This may be accomplished by restraining leptin biosynthesis (23-25) and/or by inducing leptin resistance (1,(3)(4)(5)(6)24,26). These mechanisms would be particularly well developed in individuals or animals predisposed to weight gain and diabetes (1,11,24,25,27). Consistent with the "thrifty genotype" hypothesis, this sequence of events would be tightly coupled to the onset of insulin resistance (1,11,24,28).In addition to its anorectic actions, leptin is also a potent modulator of biochemical pathways and metabolic fluxes (17-19,29 -32). In particular, we have shown that acute administration of leptin to postabsorptive rats caused a marked redistribution of intrahepatic glucose fluxes, with a marked increase in the relative contribution of gluconeogenesis and a parallel decrease in the contribution of glycogenolysis to hepatic glucose fluxes (19,32). These acute metabolic effects of leptin can be utilized to evaluate leptin sensitivity as a measurable biological response to an acute challenge with the hormone. Recent evidence in rodents (25) and humans (27) indicate that inadequate early increase in leptin secretion and biosynthesis in response to overeating may also play a role in the development of obesity and glucose intole...

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“…These results suggest that leptin overexpression in itself does not lead to leptin resistance in a non-obese model, or at least not over the duration of the present study. Thus, the leptin resistance previously reported in both obese humans 23 and animals 24,25 may not be a simple biproduct of chronic hyperleptinemia, but rather a feature specific to obesity itself. It is also possible that a combination of both chronic hyperleptinemia and obesity are required for leptin resistance, as suggested by our most recent investigation.…”

Section: Discussionmentioning

confidence: 90%

Hypothalamic delivery of doxycycline-inducible leptin gene allows for reversible transgene expression and physiological responses

et al. 2002

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Our purpose was to incorporate regulation into the recombinant adeno-associated virus encoding leptin by introducing a tet-inducible promotor. This system, TET-Ob, allows for control of leptin gene expression via doxycycline in drinking water. F344XBN rats (aged 4 months) were given a hypothalamic injection of TET-Ob or control virus. During 34 days of doxycycline (doxy) administration to all rats (STAGE 1), TET-Ob rats gained 50.7% less mass, ate 10.4% less food, and had a 77.5% reduction in serum leptin as compared with controls. Doxy was then withdrawn from half of the TET-Ob rats for 32 days (TET-Ob-OFF), while half continued to receive doxy (TET-Ob-ON) (stage 2). During stage 2, TET-

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Obesity due to high fat diet decreases the sympathetic nervous and cardiovascular responses to intracerebroventricular leptin in rats

Cited by 46 publications

References 31 publications

Pathophysiological role of leptin in obesity-related hypertension

Pathophysiological role of leptin in obesity-related hypertension

Overfeeding Rapidly Induces Leptin and Insulin Resistance

Hypothalamic delivery of doxycycline-inducible leptin gene allows for reversible transgene expression and physiological responses

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