Dual regulation of leptin secretion: intracellular energy and calcium dependence of regulated pathway

Levy, James R.; Gyarmati, J; Lesko, John M.; Adler, Robert A.; Stevens, Wayne

doi:10.1152/ajpendo.2000.278.5.e892

Cited by 80 publications

(67 citation statements)

References 41 publications

(46 reference statements)

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“…Several systemic factors that are decreased in fasting but increased in glucose-infused rats could account for the enhanced adipose leptin production. These include hyperinsulinemia (19 -21), enhanced energy flux and glucose metabolism within adipose cells (22,23), and/or the elevation of uridine diphosphate-N-acetylglucosamine, the end product of the hexosamine biosynthetic pathway, which has been recently proposed as a link between availability of nutrients and leptin expression (24). The physiological relevance of elevated leptin concentrations in glucoseinfused lean rats is not clear at present.…”

Section: Discussionmentioning

confidence: 99%

Leptin Receptor−Deficient Obese Zucker Rats Reduce Their Food Intake in Response to a Systemic Supply of Calories From Glucose

et al. 2003

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It has been established that leptin exerts a negative control on food intake, allowing one to maintain stable caloric intake over time. The aim of the present study was to investigate whether leptin regulates food intake when a supply of calories is provided by the systemic route. Experiments were carried out in leptin receptor؊ deficient obese fa/fa rats and lean Fa/fa controls. In both groups, 48 h of glucose infusion reduced food intake in proportion to caloric supply, resulting in virtually no change in total caloric intake as compared to before the infusion. This hypophagic response was reproduced without adding systemic calories, but by increasing glucose and insulin concentrations specifically in the brain through carotid artery infusion. Concomitant intracerebroventricular administration of 5-(tetradecyloxy)-2-furoic acid, an acetyl CoA carboxylase inhibitor that precludes malonyl-CoA synthesis, abolished the restriction of feeding in carotid-infused lean and obese rats. These data indicate that a supply of calories via glucose infusion induces a hypophagic response independent of leptin signaling in the rat, and support the hypothesis that a rise in central malonyl-CoA, triggered by increased glucose and insulin concentrations, participates in this adaptation. This process could contribute to the limiting of hyperphagia, primarily when leptin signaling is altered, as in the obese state. Diabetes 52:277-282, 2003 A stable body weight over time requires that caloric intake closely match energy expenditure. When excess calories are taken in, a state of positive energy balance occurs, resulting in weight gain. Tightly controlled food intake is a crucial component of energy homeostasis. This is demonstrated experimentally in rats submitted to overfeeding either by direct gastric loading (1,2) or by systemic infusion of glucose (3-5). In both situations, animals spontaneously reduce their food intake to avoid a drift in total caloric intake. A lack of adaptation to calorie overload might participate in the development of obesity. Indeed, when obesity-prone SD rats have free access to palatable food, they increase their daily food intake and fail to adapt to enhanced caloric intake (6). In this model, hyperphagia occurs despite increased circulating levels of leptin, an adipose-derived hormone that negatively controls food intake (rev. in 7). Thus, the mechanisms driving the regulatory reduction of food consumption appear to be blunted in these hyperphagic rats; part of this defect might rely on leptin resistance.A lack of leptin response is well described in obese Zucker rats (8), which bear a mutation (fa) in the leptin receptor gene (9,10). We used this rat model to address the following issues: Does a systemic supply of calories from glucose result in a decrease in food intake in the absence of leptin signaling? If so, what mechanisms are involved? In the first series of studies, age-matched obese fa/fa and lean Fa/fa rats were submitted to systemic glucose infusion with variable caloric input. In a second...

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Section: Discussionmentioning

confidence: 99%

Leptin Receptor−Deficient Obese Zucker Rats Reduce Their Food Intake in Response to a Systemic Supply of Calories From Glucose

et al. 2003

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“…Lee and S. Fried, unpublished observations). Other metabolizable hexoses or lactate also stimulate leptin release (13,41,55), suggesting that glucose metabolism into trioses or generation of ATP, rather than glucose itself, plays a role in inducing leptin production or secretion. It therefore seems likely that the inhibition of leptin release from cultured adipocyte-treated inhibitors of glucose uptake (55) were secondary to a nonspecific effect on energy status that resulted in an activation of AMPK and subsequent inhibition of general protein synthesis.…”

Section: Nutrients May Signal Alterations In Leptin Productionmentioning

confidence: 99%

Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion

Lee¹,

Fried²

2009

American Journal of Physiology-Endocrinology and Metabolism

112

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Lee M-J, Fried SK. Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion. Am J Physiol Endocrinol Metab 296: E1230 -E1238, 2009. First published March 24, 2009 doi:10.1152/ajpendo.90927.2008.-This review summarizes recent advances in our understanding of the pre-and posttranscriptional mechanisms that regulate leptin production and secretion in adipocytes. Basal leptin production is proportional to the status of energy stores, i.e., fat cell size, and this is mainly regulated by alterations in leptin mRNA levels. Leptin mRNA levels are regulated by hormones, including glucocorticoids and catecholamines, but little is known about the transcriptional mechanisms involved. Leptin synthesis and secretion is also acutely modulated in response to hormones such as insulin and the availability of metabolic fuels. Acute variations in leptin production over a time course of minutes to hours are mediated at the levels of both translation and secretion. Increases in amino acids and insulin after a meal activate the mammalian target of rapamycin (mTOR) pathway, leading to an increase in specific rates of leptin biosynthesis. Cross-talk among mTOR, PKA, and AMPactivated protein kinase pathways appears to integrate hormonal and nutrient signals that regulate leptin mRNA translation, at least in part through mechanisms involving its 5Ј-and 3Ј-untranslated regions. In addition, the rate of leptin secretion from preformed stores in response to hormonal cues is also regulated. Insulin stimulates, and adrenergic agonists inhibit, leptin secretion, and this likely contributes to variations in the magnitude of nutrition-related leptin excursions and oscillations. Overall, the study of leptin production has contributed to a deepening understanding of leptin biology and, more broadly, to our understanding of the cellular and molecular mechanisms by which the adipocyte integrates hormonal and nutrient signals to regulate adipokine production. adipose tissue; adrenergic; feeding; insulin; obesity LEPTIN IS A 16-KDA PROTEIN encoded by the obese (lep) gene that is expressed and secreted mainly by adipocytes. When energy stores are low, a fall in leptin decreases thermogenesis, promotes fatty acid (FA) over glucose oxidation, and decreases the activity of the hypothalamic pituitary adrenal and gonadal axes (1). Leptin also modulates the activities of the hematopoietic (5) and immune (52) systems, as well as angiogenesis (7).

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“…21 Briefly, pieces of frozen EWAT (B100 mg) were homogenised in TES buffer (10 Amplification was performed in an ABI Prism 7000 sequence detection system (Applied Biosystems, Foster City, CA, USA) and the results were analysed using ABI Prism 7000 software.…”

Section: Serum Analysesmentioning

confidence: 99%

“…[2][3][4][5][6][7][8] The fasting-induced reduction in leptin gene expression can be reversed by refeeding or the administration of insulin or glucose. 4,5,9 In vitro, leptin secretion is stimulated acutely by both glucose [10][11][12] and insulin [13][14][15][16] and inhibited by nonesterified fatty acids (NEFA). 17,18 It is not clear, however, whether fasting can affect the acute response of leptin to nutritional stimuli.…”

Section: Introductionmentioning

confidence: 99%

Insulin determines leptin responses during a glucose challenge in fed and fasted rats

et al. 2005

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OBJECTIVE: Leptin secretion has been shown to respond acutely to changes in blood glucose and insulin. Nutritional state also has a marked effect on both the level of circulating leptin protein and leptin gene expression. The aim of this study was to assess whether the prior nutritional state altered the leptin secretory response to an acute glucose challenge, and to determine potential mechanisms. DESIGN: Male fed or fasted rats (200-250 g) were administered a single intravenous glucose bolus (1, 4 or 7 g/kg). The serum leptin, glucose, insulin and free fatty acid responses were studied over the following 5 h. The level of leptin gene expression and leptin protein was then determined in the epididymal fat pads, and in fed and fasted untreated rats for basal comparison. RESULTS: Leptin secretion in response to glucose was suppressed in fasted rats following all glucose doses. The total leptin response was correlated with the total insulin response in all conditions (r ¼ 0.85) and with the glucose response in fed rats (r ¼ 0.69). Both leptin gene expression and leptin protein content were lower in basal fasted rats. Leptin gene expression and leptin protein content still remained lower 5 h following a glucose bolus but there was partial reversal of the effects of fasting following the 7 g/kg glucose dose. CONCLUSIONS: Leptin secretion in response to an intravenous glucose bolus was determined by the insulin response and was significantly suppressed in fasted compared to fed rats. In addition to differences in the total insulin response of the animals, lower leptin responses may be facilitated by lower levels of both leptin gene mRNA and pre-existing leptin protein in epididymal adipose tissue of fasted rats.

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Dual regulation of leptin secretion: intracellular energy and calcium dependence of regulated pathway

Cited by 80 publications

References 41 publications

Leptin Receptor−Deficient Obese Zucker Rats Reduce Their Food Intake in Response to a Systemic Supply of Calories From Glucose

Leptin Receptor−Deficient Obese Zucker Rats Reduce Their Food Intake in Response to a Systemic Supply of Calories From Glucose

Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion

Insulin determines leptin responses during a glucose challenge in fed and fasted rats

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