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 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.

scholarly journals Preoptic leptin signaling modulates energy balance independent of body temperature regulation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Sangho Yu ◽  
Helia Cheng ◽  
Marie François ◽  
Emily Qualls-Creekmore ◽  
Clara Huesing ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Body Temperature ◽  
Energy Expenditure ◽  
Ambient Temperature ◽  
Temperature Regulation ◽  
Leptin Receptor ◽  
Energy State ◽  
Body Temperature Regulation ◽  
Leptin Signaling

The adipokine leptin acts on the brain to regulate energy balance but specific functions in many brain areas remain poorly understood. Among these, the preoptic area (POA) is well known to regulate core body temperature by controlling brown fat thermogenesis, and we have previously shown that glutamatergic, long-form leptin receptor (Lepr)-expressing neurons in the POA are stimulated by warm ambient temperature and suppress energy expenditure and food intake. Here we further investigate the role of POA leptin signaling in body weight regulation and its relationship to body temperature regulation in mice. We show that POA Lepr signaling modulates energy expenditure in response to internal energy state, and thus contributes to body weight homeostasis. However, POA leptin signaling is not involved in ambient temperature-dependent metabolic adaptations. Our study reveals a novel cell population through which leptin regulates body weight.

scholarly journals Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

2009 ◽  
Vol 30 (7) ◽  
pp. 1650-1659 ◽  
Author(s):  
Jia You ◽  
Yue Yu ◽  
Lei Jiang ◽  
Wenxia Li ◽  
Xinxin Yu ◽  
...  
Keyword(s):  
Energy Balance ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Negative Regulator ◽  
Leptin Resistance ◽  
Leptin Signaling ◽  
Diet Induced Obesity ◽  
Long Form ◽  
Elevated Expression ◽  
Multiple Signaling

ABSTRACT Leptin regulates energy homeostasis through central activation of multiple signaling pathways mediated by Ob-Rb, the long form of leptin receptor. Leptin resistance underlies the pathogenic development of obesity, which is closely associated with environmental factors. To further understand the physiological function of leptin signaling mechanisms, we generated a knock-in line of mice (Y985F) expressing a mutant Ob-Rb with a phenylalanine substitution for Tyr985, one of the three intracellular tyrosines that mediate leptin's signaling actions. Surprisingly, whereas young homozygous Y985F animals were slightly leaner, they exhibit adult-onset or diet-induced obesity. Importantly, both age-dependent and diet-induced deterioration of energy balance was paralleled with pronounced leptin resistance, which was largely attributable to attenuation of leptin-responsive hypothalamic STAT3 activation as well as prominently elevated expression of hypothalamic SOCS3, a key negative regulator of leptin signaling. Thus, these results unmask distinct binary roles for Try985-mediated signaling in energy metabolism, acting as an age/diet-dependent regulatory switch to counteract age-associated or diet-induced obesity.

scholarly journals Acute Blockade of PACAP-Dependent Activity in the Ventromedial Nucleus of the Hypothalamus Disrupts Leptin-Induced Behavioral and Molecular Changes in Rats

2019 ◽  
Vol 110 (3-4) ◽  
pp. 271-281
Author(s):  
Matthew M. Hurley ◽  
Eden M. Anderson ◽  
Christopher Chen ◽  
Brian Maunze ◽  
Evan M. Hess ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Receptor Activation ◽  
Leptin Resistance ◽  
Bdnf Mrna ◽  
Leptin Signaling ◽  
Obesity And Diabetes ◽  
Stat3 Phosphorylation ◽  
Pacap Receptors

Leptin signaling pathways, stemming primarily from the hypothalamus, are necessary for maintaining normal energy homeostasis and body weight. In both rodents and humans, dysregulation of leptin signaling leads to morbid obesity and diabetes. Since leptin resistance is considered a primary factor underlying obesity, understanding the regulation of leptin signaling could lead to therapeutic tools and provide insights into the causality of obesity. While leptin actions in some hypothalamic regions such as the arcuate nuclei have been characterized, less is known about leptin activity in the hypothalamic ventromedial nuclei (VMN). Recently, pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to reduce feeding behavior and alter metabolism when administered into the VMN in a pattern similar to that of leptin. In the current study, we examined whether leptin and PACAP actions in the VMN share overlapping pathways in the regulation of energy balance. Interestingly, PACAP administration into the VMN increased STAT3 phosphorylation and SOCS3 mRNA expression, both of which are hallmarks of leptin receptor activation. In addition, BDNF mRNA expression in the VMN was increased by both leptin and PACAP administration. Moreover, antagonizing PACAP receptors fully reversed the behavioral and cellular effects of leptin injections into the VMN. Electrophysiological studies further illustrated that leptin-induced effects on VMN neurons were blocked by antagonizing PACAP receptors. We conclude that leptin dependency on PACAP signaling in the VMN suggests a potential common signaling cascade, allowing a tonically and systemically secreted neuropeptide to be more precisely regulated by central neuropeptides.

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 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 Leptin-Activity Modulators and Their Potential Pharmaceutical Applications

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1045
Author(s):  
Marianna Greco ◽  
Marzia De Santo ◽  
Alessandra Comandè ◽  
Emilia Lucia Belsito ◽  
Sebastiano Andò ◽  
...  
Keyword(s):  
Drug Targets ◽  
Leptin Receptor ◽  
Biological Activities ◽  
Reproductive Function ◽  
Leptin Resistance ◽  
Biological Functions ◽  
Leptin Signaling ◽  
Promising Strategy ◽  
Wide Range ◽  
Important Drug

Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control different processes, such as the regulation of body weight and energy expenditure, reproductive function, immune response, and bone metabolism. In addition, leptin can exert angiogenic and mitogenic actions in peripheral organs. Leptin biological activities are greatly related to its interaction with the leptin receptor. Both leptin excess and leptin deficiency, as well as leptin resistance, are correlated with different human pathologies, such as autoimmune diseases and cancers, making leptin and leptin receptor important drug targets. The development of leptin signaling modulators represents a promising strategy for the treatment of cancers and other leptin-related diseases. In the present manuscript, we provide an update review about leptin-activity modulators, comprising leptin mutants, peptide-based leptin modulators, as well as leptin and leptin receptor specific monoclonal antibodies and nanobodies.

Programming of rat adrenal medulla by neonatal hyperleptinemia: adrenal morphology, catecholamine secretion, and leptin signaling pathway

2010 ◽  
Vol 298 (5) ◽  
pp. E941-E949 ◽  
Author(s):  
I. H. Trevenzoli ◽  
C. R. Pinheiro ◽  
E. P. S. Conceição ◽  
E. Oliveira ◽  
M. C. F. Passos ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Direct Effect ◽  
Leptin Receptor ◽  
Fold Increase ◽  
Leptin Resistance ◽  
Adult Rats ◽  
Leptin Signaling ◽  
Tyrosine Kinase 2 ◽  
Lower Expression

Leptin serum concentration in early life is an important factor for adequate future development of the offspring. Previously, we demonstrated that hyperleptinemia on lactation programmed for hyperleptinemia, central leptin resistance with lower expression of the long form of leptin receptor at hypothalamus, and higher medullary catecholamine levels with cardiovascular consequences at adulthood. The central objective of this study was to determine the direct effect of leptin on adrenal medullary function of adult rats that were leptin treated during lactation. Adrenal morphology was also accessed. Recombinant murine leptin was injected in the pups during the first 10 days of life (group L, leptin-programmed) or at adulthood during 6 days (group LC). The controls of both experiments received saline (groups C and CC). Both treatments resulted in hyperleptinemia at 150 days old (+78% and 2-fold increase, respectively; P < 0.05). Programmed animals showed hypertrophy of adrenal and higher adrenal catecholamine content at 150 days old (3-fold increase, P < 0.05), and no changes were observed in the LC group. However, LC rats had lower adrenal content of tyrosine hydroxylase (−17%, P < 0.05). Leptin-programmed rats had a lower response to leptin in vitro stimulation (−22%, P < 0.05) and lower expression of key proteins of the leptin signaling pathway, leptin receptor and janus tyrosine kinase 2 in the medullas (−61% and −29%, respectively, P < 0.05). However, they presented higher expression of phosphorylated signal transducer and activator of transcription 3 (+2-fold, P < 0.05). Leptin treatment at adulthood did not affect these parameters. The higher catecholamine synthesis and secretion in the leptin-programmed rats observed in our previous study does not seem to be a consequence of the direct effect of leptin on the medullas. We suggest that the hyperleptinemia of the programmed animals increases adrenal medullary function through sympathetic nervous system activation. In conclusion, high leptin levels on lactation program the activity of the sympathoadrenal system at adulthood that may contribute to the development of adult chronic diseases such as hypertension.

scholarly journals Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions

2018 ◽  
Vol 108 (2) ◽  
pp. 132-141
Author(s):  
Clara Roujeau ◽  
Ralf Jockers ◽  
Julie Dam
Keyword(s):  
Signaling Pathways ◽  
Intracellular Trafficking ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
Human Obesity ◽  
Leptin Signaling ◽  
Diet Induced Obesity ◽  
Important Regulator ◽  
Neuronal Plasma Membrane ◽  
Underlying Mechanisms

Endospanin 1 (Endo1), a protein encoded in humans by the same gene than the leptin receptor (ObR), and increased by diet-induced obesity, is an important regulator of ObR trafficking and cell surface exposure, determining leptin signaling strength. Defective intracellular trafficking of the leptin receptor to the neuronal plasma membrane has been proposed as a mechanism underlying the development of leptin resistance observed in human obesity. More recently, Endo1 has emerged as a mediator of “selective leptin resistance.” The underlying mechanisms of the latter are not completely understood, but the possibility of differential activation of leptin signaling pathways was suggested among others. In this respect, the expression level of Endo1 is crucial for the appropriate balance between different leptin signaling pathways and leptin functions in the hypothalamus and is likely participating in selective leptin resistance for the control of energy and glucose homeostasis.

scholarly journals Changes in Expression of the Genes for the Leptin Signaling in Hypothalamic-Pituitary Selected Areas and Endocrine Responses to Long-Term Manipulation in Body Weight and Resistin in Ewes

2020 ◽  
Vol 21 (12) ◽  
pp. 4238
Author(s):  
Dorota Anna Zieba ◽  
Weronika Biernat ◽  
Malgorzata Szczesna ◽  
Katarzyna Kirsz ◽  
Justyna Barć ◽  
...  
Keyword(s):  
Body Weight ◽  
Leptin Receptor ◽  
Fat Body ◽  
Density Lipoprotein ◽  
Reproductive Hormones ◽  
Leptin Resistance ◽  
Nonesterified Fatty Acid ◽  
Cytokine Signaling ◽  
Leptin Signaling

Both long-term undernutrition and overnutrition disturb metabolic balance, which is mediated partially by the action of two adipokines, leptin and resistin (RSTN). In this study, we manipulated the diet of ewes to produce either a thin (lean) or fat (fat) body condition and investigated how RSTN affects endocrine and metabolic status under different leptin concentrations. Twenty ewes were distributed into four groups (n = 5): the lean and fat groups were administered with saline (Lean and Fat), while the Lean-R (Lean-Resistin treated) and Fat-R (Fat-Resistin treated) groups received recombinant bovine resistin. Plasma was assayed for LH, FSH, PRL, RSTN, leptin, GH, glucose, insulin, total cholesterol, nonesterified fatty acid (NEFA), high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides. Expression levels of a suppressor of cytokine signaling (SOCS-3) and the long form of the leptin receptor (LRb) were determined in selected brain regions, such as the anterior pituitary, hypothalamic arcuate nucleus, preoptic area and ventro- and dorsomedial nuclei. The results indicate long-term alterations in body weight affect RSTN-mediated effects on metabolic and reproductive hormones concentrations and the expression of leptin signaling components: LRb and SOCS-3. This may be an adaptive mechanism to long-term changes in adiposity during the state of long-day leptin resistance.

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