Endogenous Leptin Signaling in the Caudal Nucleus Tractus Solitarius and Area Postrema Is Required for Energy Balance Regulation

Hayes, Matthew R.; Skibicka, Karolina P.; Leichner, Theresa M.; Guarnieri, Douglas J.; DiLeone, Ralph J.; Bence, Kendra K.; Grill, Harvey J.

doi:10.1016/j.cmet.2009.10.009

Cited by 216 publications

(192 citation statements)

References 36 publications

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“…Most studies focus on hypothalamic LepRb signaling to explain leptin's effects on food intake and BW regulation (eg arcuate nucleus, LH, VMH) (Balthasar et al, 2004;Dhillon et al, 2006;Leinninger et al, 2009). However, recent findings strongly suggest that leptin's contribution to energy balance control is mediated by endogenous signaling that is anatomically distributed (Grill, 2010) across multiple brain regions that include the hindbrain (eg nucleus tractus solitarius (NTS) (Hayes et al, 2010)) and midbrain (eg ventral tegmental area (VTA) (Fulton et al, 2006;Hommel et al, 2006;Morton et al, 2009)) nuclei. Here, we identify the hippocampus, a forebrain structure traditionally associated with learning and memory function, as a novel CNS site of relevance to leptin-mediated control of food intake.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of leptin signaling in the hypothalamus (Balthasar et al, 2004;Dhillon et al, 2006;Leinninger et al, 2009) and the caudal brainstem (Grill et al, 2002;Huo et al, 2007;Hayes et al, 2010) is established for the homeostatic or need-based control of food intake. However, given that the excessive food intake that contributes to human obesity is generally not driven by metabolic need, it is critical to examine and better define the neural basis of nonhomeostatic controls on food intake.…”

Section: Introductionmentioning

confidence: 99%

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Hippocampal Leptin Signaling Reduces Food Intake and Modulates Food-Related Memory Processing

Kanoski

Hayes

Greenwald

et al. 2011

Neuropsychopharmacol

137

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The increase in obesity prevalence highlights the need for a more comprehensive understanding of the neural systems controlling food intake; one that extends beyond food intake driven by metabolic need and considers that driven by higher-order cognitive factors. The hippocampus, a brain structure involved in learning and memory function, has recently been linked with food intake control. Here we examine whether administration of the adiposity hormone leptin to the dorsal and ventral sub-regions of the hippocampus influences food intake and memory for food. Leptin (0.1 mg) delivered bilaterally to the ventral hippocampus suppressed food intake and body weight measured 24 h after administration; a higher dose (0.4 mg) was needed to suppress intake following dorsal hippocampal delivery. Leptin administration to the ventral but not dorsal hippocampus blocked the expression of a conditioned place preference for food and increased the latency to run for food in an operant runway paradigm. Additionally, ventral but not dorsal hippocampal leptin delivery suppressed memory consolidation for the spatial location of food, whereas hippocampal leptin delivery had no effect on memory consolidation in a non-spatial appetitive response paradigm. Collectively these findings indicate that ventral hippocampal leptin signaling contributes to the inhibition of food-related memories elicited by contextual stimuli. To conclude, the results support a role for hippocampal leptin signaling in the control of food intake and food-related memory processing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hippocampal Leptin Signaling Reduces Food Intake and Modulates Food-Related Memory Processing

Kanoski

Hayes

Greenwald

et al. 2011

Neuropsychopharmacol

137

View full text Add to dashboard Cite

show abstract

“…(1) Leptin receptors are expressed in peripheral tissues, including skeletal muscle, bone, and cartilage, but a primary target of leptin binding is the brain, specifically the hypothalamus and hindbrain. (2) Leptin's effects on bone are mediated via a central neuroendocrine signaling pathway, as well as directly on bone marrow stem cells to enhance their differentiation to osteoblasts and inhibit their differentiation to adipocytes. (3)(4)(5)(6)(7)(8) There are contradictory published data regarding the effects of leptin on bone mass in rodents.…”

Section: Introductionmentioning

confidence: 99%

Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice

Bartell

Rayalam

Ambati

et al. 2011

Journal of Bone and Mineral Research

139

117

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Both central and peripheral leptin administrations reduce body weight, food intake, and adiposity in ob/ob mice. In this study we compared effects of intracerebroventricular (ICV) and subcutaneous (SC) administration of leptin on bone metabolism in the appendicular and axial skeleton and adipose tissue gene expression and determined the effects of ICV leptin on bone marrow gene expression in ob/ob mice. In experiment 1, leptin (1.5 or 0.38 mg/d) or control was continuously injected ICV for 12 days. Gene expression analysis of femoral bone marrow stromal cells showed that expression of genes associated with osteogenesis was increased after ICV injection, whereas those associated with osteoclastogenesis, adipogenesis, and adipocyte lipid storage were decreased. In experiment 2, leptin was injected continuously ICV (0.0 or 1.5 mg/d) or SC (0.0 or 10 mg/d) for 12 days. In both experiments, regardless of mode of administration, leptin decreased body weight, food intake, and body fat and increased muscle mass, bone mineral density, bone mineral content, bone area, marrow adipocyte number, and mineral apposition rate. Serum insulin was decreased, whereas serum osteocalcin, insulin-like growth factor 1, osteoprotegerin, pyridinoline, and receptor activator of nuclear factor kB ligand concentrations were increased. In experiment 2, expression of genes in adipose tissue associated with apoptosis, lipid mobilization, insulin sensitivity, and thermogenesis was increased, whereas expression of genes associated with cell differentiation and maturation was decreased regardless of mode of administration. Thus ICV injection of leptin promotes expression of pro-osteogenic factors in bone marrow, leading to enhanced bone formation in ob/ob mice. ß

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“…It has been demonstrated recently that the absence of LepR signaling in other neuronal populations, such as the ventromedial nucleus (17), the ventral tegmental area (22), and the caudal nucleus tractus solitarius and area postrema (21), is also important in the regulation of energy homeostasis. Given that VAN play a major role in the regulation of meal size and duration and express leptin receptors, we hypothesized that leptin resistance could also occur in VAN in diet-induced obesity.…”

mentioning

confidence: 99%

Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

Lartigue

Serre

Espero

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

154

142

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de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE. Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. Am J Physiol Endocrinol Metab 301: E187-E195, 2011. First published April 26, 2011; doi:10.1152/ajpendo.00056.2011.-Ingestion of high-fat, high-calorie diets is associated with hyperphagia, increased body fat, and obesity. The mechanisms responsible are currently unclear; however, altered leptin signaling may be an important factor. Vagal afferent neurons (VAN) integrate signals from the gut in response to ingestion of nutrients and express leptin receptors. Therefore, we tested the hypothesis that leptin resistance occurs in VAN in response to a high-fat diet. Sprague-Dawley rats, which exhibit a bimodal distribution of body weight gain, were used after ingestion of a high-fat diet for 8 wk. Body weight, food intake, and plasma leptin levels were measured. Leptin signaling was determined by immunohistochemical localization of phosphorylated STAT3 (pSTAT3) in cultured VAN and by quantifaction of pSTAT3 protein levels by Western blot analysis in nodose ganglia and arcuate nucleus in vivo. To determine the mechanism of leptin resistance in nodose ganglia, cultured VAN were stimulated with leptin alone or with lipopolysaccharide (LPS) and SOCS-3 expression measured. SOCS-3 protein levels in VAN were measured by Western blot following leptin administration in vivo. Leptin resulted in appearance of pSTAT3 in VAN of low-fat-fed rats and rats resistant to diet-induced obesity but not diet-induced obese (DIO) rats. However, leptin signaling was normal in arcuate neurons. SOCS-3 expression was increased in VAN of DIO rats. In cultured VAN, LPS increased SOCS-3 expression and inhibited leptin-induced pSTAT3 in vivo. We conclude that VAN of diet-induced obese rats become leptin resistant; LPS and SOCS-3 may play a role in the development of leptin resistance.lipopolysaccharide; high-fat diet; suppressor of cytokine signaling-3 THE GUT PLAYS A CRUCIAL ROLE in sensing luminal contents that is important for the efficient digestion and absorption of ingested nutrients but also in integration of other physiological processes that regulate metabolism and energy expenditure, such as pancreatic ␤-cell function, hepatic function, and also food intake (34). In response to the presence or absence of food, enteroendocrine cells of the gut release anorexic or orexigenic hormones, respectively. The first site of integration of these signals occurs at the level of vagal afferent neurons (VAN), which project to and stimulate second-order neurons in the dorsal vagal complex of the hindbrain (27). VAN express receptors for many of the anorexigenic and orexigenic hormones released from the gut wall and mediate changes in gastrointestinal function and food intake in response to luminal nutrients (18).Leptin is a gut and adipose tissue-derived hormone that regulates a range of biological functions and processes, including energy intake and expenditure, body fat, neuroendocrine systems...

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Endogenous Leptin Signaling in the Caudal Nucleus Tractus Solitarius and Area Postrema Is Required for Energy Balance Regulation

Cited by 216 publications

References 36 publications

Hippocampal Leptin Signaling Reduces Food Intake and Modulates Food-Related Memory Processing

Hippocampal Leptin Signaling Reduces Food Intake and Modulates Food-Related Memory Processing

Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice

Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

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