scholarly journals The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure

2007 ◽  
Vol 193 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Hiroyuki Shimizu ◽  
Kinji Inoue ◽  
Masatomo Mori
Keyword(s):  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Signaling System ◽  
Leptin Signaling ◽  
Melanocyte Stimulating Hormone ◽  
Hypothalamic Nuclei ◽  
Hypothalamic Arcuate Nucleus ◽  
Melanocortin Signaling ◽  
The Brain

The brain hypothalamus coordinates extra-hypothalamic regions to maintain energy homeostasis through the regulation of food intake and energy expenditure. A number of anorexigenic and orexigenic molecules in the hypothalamic nuclei participate in the control of energy homeostasis. Leptin and pro-opiomelanocortin (POMC)-derived α-melanocyte-stimulating hormone are key anorectic molecules, and the leptin receptor and POMC gene are both expressed in the hypothalamic arcuate nucleus. Although it has been considered that melanocortin signaling is localized downstream to leptin signaling, data have accumulated to support the concept of a leptin-independent melanocortin signaling system. We focus on and review the melanocortin signaling system that functions dependently or independently of leptin signaling in the regulation of energy homeostasis.

scholarly journals Nutritional Influences on Reproductive Neuroendocrine Output: Insulin, Leptin, and Orexigenic Neuropeptide Signaling in the Ovine Hypothalamus

Endocrinology ◽  
2007 ◽  
Vol 148 (11) ◽  
pp. 5313-5322 ◽  
Author(s):  
David W. Miller ◽  
Joanne L. Harrison ◽  
Ellen J. Bennett ◽  
Patricia A. Findlay ◽  
Clare L. Adam
Keyword(s):  
Gene Expression ◽  
Neuropeptide Y ◽  
Leptin Receptor ◽  
Nutritional Influences ◽  
Hypothalamic Arcuate Nucleus ◽  
Melanocortin Signaling ◽  
Neuroendocrine Responses ◽  
Peptide Gene ◽  
Plasma Leptin ◽  
The Brain

This study investigated how changing nutritional status may alter reproductive neuroendocrine (LH) output via circulating leptin and insulin signaling through orexigenic hypothalamic pathways. Thin sheep were given an increasing nutritional plane (INP), sheep with intermediate adiposity a static nutritional plane (SNP), and fat sheep a decreasing nutritional plane (DNP) for 6 wk. Mean group adiposities converged by wk 6, LH output increased in INP, remained unchanged in SNP, and decreased in DNP sheep. Plasma and cerebrospinal fluid (CSF) insulin and plasma leptin concentrations increased in INP but did not change in the SNP and DNP groups. In INP sheep, LH output correlated positively with adiposity and plasma and CSF insulin concentrations and negatively with orexigenic neuropeptide Y gene expression in the hypothalamic arcuate nucleus (ARC). In DNP sheep, LH output correlated positively with adiposity, CSF leptin concentrations, and ARC proopiomelanocortin gene expression and negatively with leptin receptor (OB-Rb) and agouti-related peptide gene expression in the ARC. These data are consistent with the feedback response to an increasing nutritional plane being mediated by increasing circulating insulin entering the brain and stimulating LH via inhibition of hypothalamic neuropeptide Y and the response to a decreasing nutritional plane being mediated by altered hypothalamic leptin signaling brought about by increased OB-Rb expression and decreased melanocortin signaling. Because end point adiposity was similar yet LH output was different, the hypothalamus apparently retains a nutritional memory, based on changes in orexigenic neuropeptide expression, that influences contemporary neuroendocrine responses.

scholarly journals Leptin Signaling Is Required for Leucine Deprivation-enhanced Energy Expenditure

2013 ◽  
Vol 289 (3) ◽  
pp. 1779-1787 ◽  
Author(s):  
Qian Zhang ◽  
Bin Liu ◽  
Ying Cheng ◽  
Qingshu Meng ◽  
Tingting Xia ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Normal Diet ◽  
Leptin Resistance ◽  
High Fat ◽  
Leptin Signaling ◽  
Fat Loss ◽  
Stimulation Of

Leptin signaling in the hypothalamus is crucial in energy homeostasis. We have previously shown that dietary deprivation of the essential amino acid leucine in mice stimulates fat loss by increasing energy expenditure. The involvement of leptin signaling in this regulation, however, has not been reported. Here, we show that leucine deprivation promotes leptin signaling in mice maintained on an otherwise normal diet and restores leptin responses in mice maintained on a high fat diet, a regimen known to induce leptin resistance. In addition, we found that leucine deprivation stimulated energy expenditure, and fat loss was largely blocked in db/db mice homozygous for a mutation in leptin receptor and a knock-in mouse line Y3F with abrogation of leptin receptor Tyr1138-mediated signal transducer and activator transcript 3 signaling. Overall, our studies describe a novel link between hypothalamic leptin signaling and stimulation of energy expenditure under leucine deprivation.

Cross-talk between estrogen and leptin signaling in the hypothalamus

2008 ◽  
Vol 294 (5) ◽  
pp. E817-E826 ◽  
Author(s):  
Qian Gao ◽  
Tamas L. Horvath
Keyword(s):  
Energy Balance ◽  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Steroid Hormone ◽  
The United States ◽  
Gonadal Steroid ◽  
Leptin Signaling ◽  
Downstream Signaling ◽  
Reproductive Axis ◽  
The Brain

Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that results in the accumulation of body fat, is a major risk factor for various diseases, including diabetes, cardiovascular disease, and cancer. In the United States, more than half of adults are overweight, and this number continues to increase. The adipocyte-secreted hormone leptin and its downstream signaling mediators play crucial roles in the regulation of energy balance. Leptin decreases feeding while increasing energy expenditure and permitting energy-intensive neuroendocrine processes, such as reproduction. Thus, leptin also modulates the neuroendocrine reproductive axis. The gonadal steroid hormone estrogen plays a central role in the regulation of reproduction and also contributes to the regulation of energy balance. Estrogen deficiency promotes feeding and weight gain, and estrogen facilitates, and to some extent mimics, some actions of leptin. In this review, we examine the functions of estrogen and leptin in the brain, with a focus on mechanisms by which leptin and estrogen cooperate in the regulation of energy homeostasis.

scholarly journals Recent advances in understanding leptin signaling and leptin resistance

2009 ◽  
Vol 297 (6) ◽  
pp. E1247-E1259 ◽  
Author(s):  
David L. Morris ◽  
Liangyou Rui
Keyword(s):  
Endoplasmic Reticulum ◽  
Body Weight ◽  
Risk Factor ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
Leptin Signaling ◽  
Long Form ◽  
The Brain ◽  
Primary Risk Factor

The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance.

scholarly journals Lztfl1/BBS17 controls energy homeostasis by regulating the leptin signaling in the hypothalamic neurons

2018 ◽  
Vol 10 (5) ◽  
pp. 402-410 ◽  
Author(s):  
Qun Wei ◽  
Yi-Feng Gu ◽  
Qing-Jun Zhang ◽  
Helena Yu ◽  
Yan Peng ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Signaling Pathway ◽  
Energy Homeostasis ◽  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Leptin Receptor ◽  
Energy State ◽  
Leptin Resistance ◽  
Leptin Signaling ◽  
Wide Range

Abstract Leptin receptor (LepRb) signaling pathway in the hypothalamus of the forebrain controls food intake and energy expenditure in response to an altered energy state. Defects in the LepRb signaling pathway can result in leptin-resistance and obesity. Leucine zipper transcription factor like 1 (Lztfl1)/BBS17 is a member of the Bardet–Biedl syndrome (BBS) gene family. Human BBS patients have a wide range of pathologies including obesity. The cellular and molecular mechanisms underlying Lztfl1-regulated obesity are unknown. Here, we generated Lztfl1f/f mouse model in which Lztfl1 can be deleted globally and in tissue-specific manner. Global Lztfl1 deficiency resulted in pleiotropic phenotypes including obesity. Lztfl1−/− mice are hyperphagic and showed similar energy expenditure as WT littermates. The obese phenotype of Lztfl1−/− mice is caused by the loss of Lztfl1 in the brain but not in the adipocytes. Lztfl1−/− mice are leptin-resistant. Inactivation of Lztfl1 abolished phosphorylation of Stat3 in the LepRb signaling pathway in the hypothalamus upon leptin stimulation. Deletion of Lztfl1 had no effect on LepRb membrane localization. Furthermore, we observed that Lztfl1−/− mouse embryonic fibroblasts (MEFs) have significantly longer cilia than WT MEFs. We identified several proteins that potentially interact with Lztfl1. As these proteins are known to be involved in regulation of actin/cytoskeleton dynamics, we suggest that Lztfl1 may regulate leptin signaling and ciliary structure via these proteins. Our study identified Lztfl1 as a novel player in the LepRb signaling pathway in the hypothalamus that controls energy homeostasis.

scholarly journals Expression of a hypomorphic Pomc allele alters leptin dynamics during late pregnancy

2020 ◽  
Vol 245 (1) ◽  
pp. 115-127 ◽  
Author(s):  
Hui Yu ◽  
Zoe Thompson ◽  
Sylee Kiran ◽  
Graham L Jones ◽  
Lakshmi Mundada ◽  
...  
Keyword(s):  
Fat Mass ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Late Pregnancy ◽  
Placental Development ◽  
Hypomorphic Mutation ◽  
Protein Levels ◽  
Maximal Arc ◽  
Hypothalamic Arcuate Nucleus ◽  
Pregnancy And Lactation

Proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC) are essential for normal energy homeostasis. Maximal ARC Pomc transcription is dependent on neuronal Pomc enhancer 1 (nPE1), located 12 kb upstream from the promoter. Selective deletion of nPE1 in mice decreases ARC Pomc expression by 70%, sufficient to induce mild obesity. Because nPE1 is located exclusively in the genomes of placental mammals, we questioned whether its hypomorphic mutation would also alter placental Pomc expression and the metabolic adaptations associated with pregnancy and lactation. We assessed placental development, pup growth, circulating leptin and expression of Pomc, Agrp and alternatively spliced leptin receptor (LepR) isoforms in the ARC and placenta of Pomc∆1/∆1 and Pomc+/+ dams. Despite indistinguishable body weights, lean mass, food intake, placental histology and Pomc expression and overall pregnancy outcomes between the genotypes, Pomc ∆1/∆1 females had increased pre-pregnancy fat mass that paradoxically decreased to control levels by parturition. However, Pomc∆1/∆1 dams had exaggerated increases in circulating leptin, up to twice of that of the typically elevated levels in Pomc+/+ mice at the end of pregnancy, despite their equivalent fat mass. Pomc∆1/∆1dams also had increased placental expression of soluble leptin receptor (LepRe), although the protein levels of LEPRE in circulation were the same as Pomc+/+ controls. Together, these data suggest that the hypomorphic Pomc∆1/∆1 allele is responsible for the perinatal super hyperleptinemia of Pomc∆1/∆1 dams, possibly due to upregulated leptin secretion from individual adipocytes.

scholarly journals Sleep-wake regulation is altered in leptin-resistant (db/db) genetically obese and diabetic mice

2008 ◽  
Vol 295 (6) ◽  
pp. R2059-R2066 ◽  
Author(s):  
A. D. Laposky ◽  
M. A. Bradley ◽  
D. L. Williams ◽  
J. Bass ◽  
F. W. Turek
Keyword(s):  
Energy Metabolism ◽  
Eye Movement ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Sleep Time ◽  
Rapid Eye Movement ◽  
Sleep Regulation ◽  
Compensatory Response ◽  
Leptin Signaling ◽  
Obesity And Diabetes

Recent epidemiological and clinical studies indicate that the control of sleep-wake states may be an important factor in the regulation of energy metabolism. Leptin is a peripherally synthesized hormone that has critical signaling properties in the brain for the control of long-term energy homeostasis. In this study, we examined the hypothesis that leptin signaling exerts a role in sleep-wake regulation and that leptin may represent an important mechanistic link in the coordination of sleep-wake states and metabolism. Sleep-wake patterns were recorded in a genetic mouse model of obesity and diabetes, the db/db mouse, which harbors a mutation in a particular isoform of the leptin receptor (long form, LRb). We found that db/db mice exhibit a variety of alterations in sleep regulation, including an increase in overall sleep time, a dramatic increase in sleep fragmentation, attenuated diurnal rhythmicity in rapid eye movement sleep and non-rapid eye movement EEG delta power (a measure of sleep homeostatic drive), and a decrease in the compensatory response to acute (i.e., 6 h) sleep deprivation. The db/db mice also generated low amounts of locomotor activity and a reduction in the diurnal rhythm of activity. These results indicate that impaired leptin signaling has deleterious effects on the regulation of sleep amount, sleep architecture, and temporal consolidation of these arousal states. In summary, leptin may represent an important molecular component in the integration of sleep, circadian rhythms, and energy metabolism.

scholarly journals Endocrine factors in the hypothalamic regulation of food intake in females: a review of the physiological roles and interactions of ghrelin, leptin, thyroid hormones, oestrogen and insulin

2011 ◽  
Vol 24 (1) ◽  
pp. 132-154 ◽  
Author(s):  
V. Somogyi ◽  
A. Gyorffy ◽  
T. J. Scalise ◽  
D. S. Kiss ◽  
G. Goszleth ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Expenditure ◽  
Thyroid Hormones ◽  
Energy Homeostasis ◽  
The Body ◽  
Feedback Information ◽  
Hypothalamic Regulation ◽  
The Individual ◽  
Desire To Eat ◽  
The Brain

Controlling energy homeostasis involves modulating the desire to eat and regulating energy expenditure. The controlling machinery includes a complex interplay of hormones secreted at various peripheral endocrine endpoints, such as the gastrointestinal tract, the adipose tissue, thyroid gland and thyroid hormone-exporting organs, the ovary and the pancreas, and, last but not least, the brain itself. The peripheral hormones that are the focus of the present review (ghrelin, leptin, thyroid hormones, oestrogen and insulin) play integrated regulatory roles in and provide feedback information on the nutritional and energetic status of the body. As peripheral signals, these hormones modulate central pathways in the brain, including the hypothalamus, to influence food intake, energy expenditure and to maintain energy homeostasis. Since the growth of the literature on the role of various hormones in the regulation of energy homeostasis shows a remarkable and dynamic expansion, it is now becoming increasingly difficult to understand the individual and interactive roles of hormonal mechanisms in their true complexity. Therefore, our goal is to review, in the context of general physiology, the roles of the five best-known peripheral trophic hormones (ghrelin, leptin, thyroid hormones, oestrogen and insulin, respectively) and discuss their interactions in the hypothalamic regulation of food intake.

Neuronal deletion of Lepr elicits diabesity in mice without affecting cold tolerance or fertility

2005 ◽  
Vol 289 (3) ◽  
pp. E403-E411 ◽  
Author(s):  
Julie E. McMinn ◽  
Shun-Mei Liu ◽  
Hong Liu ◽  
Ioannis Dragatsis ◽  
Paula Dietrich ◽  
...  
Keyword(s):  
Cold Tolerance ◽  
Leptin Receptor ◽  
Serum Insulin ◽  
Tolerance Test ◽  
Serum Leptin ◽  
Leptin Signaling ◽  
Cold Tolerant ◽  
Total Fat ◽  
The Brain ◽  
Specific Deletion

Leptin signaling in the brain regulates energy intake and expenditure. To test the degree of functional neuronal leptin signaling required for the maintenance of body composition, fertility, and cold tolerance, transgenic mice expressing Cre in neurons ( CaMKIIα-Cre) were crossed to mice carrying a floxed leptin receptor ( Lepr) allele to generate mice with neuron-specific deletion of Lepr in ∼50% ( C F/F mice) and ∼75% ( C Δ17/F mice) of hypothalamic neurons. Leptin receptor (LEPR)-deficient mice ( Δ17/Δ17) with heat-shock-Cre-mediated global Lepr deletion served as obese controls. At 16 wk, male C F/F, C Δ17/F, and Δ17/Δ17 mice were 13.2 ( P < 0.05), 45.0, and 55.9% ( P < 0.001) heavier, respectively, than lean controls, whereas females showed 31.6, 68.8, and 160.7% increases in body mass ( P < 0.001). Significant increases in total fat mass ( C F/F: P < 0.01; C Δ17/F and Δ17/Δ17: P < 0.001 vs. sex-matched, lean controls), and serum leptin concentrations ( P < 0.001 vs. controls) were present in proportion to Lepr deletion. Male C Δ17/F mice had significant elevations in basal serum insulin concentrations ( P < 0.001 vs. controls) and were glucose intolerant, as measured by glucose tolerance test (AUC P < 0.01 vs. controls). In contrast with previous observations in mice null for LEPR signaling, C F/F and C Δ17/F mice were fertile and cold tolerant. These findings support the hypothesis that body weight, adiposity, serum leptin concentrations, and glucose intolerance are proportional to hypothalamic LEPR deficiency. However, fertility and cold tolerance remain intact unless hypothalamic LEPR deficiency is complete.

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