MAPK Erk5 in Leptin Receptor‒Expressing Neurons Controls Body Weight and Systemic Energy Homeostasis in Female Mice

Abstract Extracellular signal-regulated kinase 5 (Erk5), a member of the MAPK family, is specifically phosphorylated and activated by MAPK/Erk kinase-5. Although it has been implicated in odor discrimination and long-term memory via its expression in the central nervous system, little is known regarding the physiological importance of neuronal Erk5 in body weight and energy homeostasis. In the current study, systemic insulin injection significantly induced phosphorylation of Erk5 in the hypothalamus. Moreover, Erk5 deficiency in leptin receptor (LepR)‒expressing neurons led to an obesity phenotype, with increased white adipose tissue mass due to increased adipocyte size, only in female mice fed a normal chow diet. Furthermore, Erk5 deficiency in LepR-expressing neurons showed impaired glucose tolerance along with decreased physical activity, food intake, and energy expenditure. These results suggest that Erk5 controls body weight and systemic energy homeostasis probably via its expression in hypothalamic neurons in female mice, thereby providing a target for metabolic diseases such as obesity and type 2 diabetes mellitus.

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Leptin Signaling Is Not Required for Anorexigenic Estradiol Effects in Female Mice

Endocrinology ◽

10.1210/en.2015-1594 ◽

2016 ◽

Vol 157 (5) ◽

pp. 1991-2001 ◽

Cited By ~ 9

Author(s):

Joon S. Kim ◽

Mohammed Z. Rizwan ◽

Deborah J. Clegg ◽

Greg M. Anderson

Keyword(s):

Body Weight ◽

Cross Talk ◽

Metabolic Regulation ◽

Leptin Receptor ◽

Fluorescent Protein ◽

Estrogen Receptor Α ◽

Female Mice ◽

Leptin Sensitivity ◽

Stat3 Phosphorylation ◽

Green Fluorescent

Abstract Estradiol and leptin are critical hormones in the regulation of body weight. The aim of this study was to determine whether this cross talk between leptin receptor (LepRb) and estrogen receptor-α (ERα) signaling is critical for estradiol's anorexigenic effects. Leprb-Cre mice were crossed with Cre-dependent Tau-green fluorescent protein (GFP) reporter, Stat3-flox or Erα-flox mice to generate female mice with GFP expression, signal transducer and activator of transcription 3 (STAT3) knockout (KO), or ERα KO, specifically in LepRb-expressing cells. The proportion of Leprb-GFP cells colocalizing ERα was high (∼80%) in the preoptic area but low (∼10%) in the mediobasal hypothalamus, suggesting that intracellular cross talk between these receptors is minimal for metabolic regulation. To test whether estradiol enhanced arcuate leptin sensitivity, ovarectomized mice received varying levels of estradiol replacement. Increasing estrogenic states did not increase the degree of leptin-induced STAT3 phosphorylation. LepRb-specific STAT3 KO mice and controls were ovarectomized and given either chronic estradiol or vehicle treatment to test whether STAT3 is required for estrogen-induced body weight suppression. Both groups of estradiol-treated mice showed an equivalent reduction in body weight and fat content compared with vehicle controls. Finally, mice lacking ERα specifically in LepRb-expressing neurons also showed no increase in body weight or impairments in metabolic function compared with controls, indicating that estradiol acts independently of leptin-responsive cells to regulate body weight. However, fecundity was impaired in in Leprb-ERα KO females. Contrary to the current dogma, we report that estradiol has minimal direct actions on LepRb cells in the mediodasal hypothalamus and that its anorexigenic effects can occur entirely independently of LepRb-STAT3 signaling in female mice.

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Collective and Individual Functions of Leptin Receptor Modulated Neurons Controlling Metabolism and Ingestion

Endocrinology ◽

10.1210/en.2007-1132 ◽

2007 ◽

Vol 149 (4) ◽

pp. 1773-1785 ◽

Cited By ~ 222

Author(s):

Esther van de Wall ◽

Rebecca Leshan ◽

Allison W. Xu ◽

Nina Balthasar ◽

Roberto Coppari ◽

...

Keyword(s):

Body Weight ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Leptin Receptor ◽

Receptor Gene ◽

Normal Glucose Tolerance ◽

Adult Mice ◽

Normal Glucose ◽

High Doses ◽

Agouti Gene

Two known types of leptin-responsive neurons reside within the arcuate nucleus: the agouti gene-related peptide (AgRP)/neuropeptide Y (NPY) neuron and the proopiomelanocortin (POMC) neuron. By deleting the leptin receptor gene (Lepr) specifically in AgRP/NPY and/or POMC neurons of mice, we examined the several and combined contributions of these neurons to leptin action. Body weight and adiposity were increased by Lepr deletion from AgRP and POMC neurons individually, and simultaneous deletion in both neurons (A+P LEPR-KO mice) further increased these measures. Young (periweaning) A+P LEPR-KO mice exhibit hyperphagia and decreased energy expenditure, with increased weight gain, oxidative sparing of triglycerides, and increased fat accumulation. Interestingly, however, many of these abnormalities were attenuated in adult animals, and high doses of leptin partially suppress food intake in the A+P LEPR-KO mice. Although mildly hyperinsulinemic, the A+P LEPR-KO mice displayed normal glucose tolerance and fertility. Thus, AgRP/NPY and POMC neurons each play mandatory roles in aspects of leptin-regulated energy homeostasis, high leptin levels in adult mice mitigate the importance of leptin-responsiveness in these neurons for components of energy balance, suggesting the presence of other leptin-regulated pathways that partially compensate for the lack of leptin action on the POMC and AgRP/NPY neurons.

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Selective inhibition of CBP/p300 HAT by A-485 results in suppression of lipogenesis and hepatic gluconeogenesis

Cell Death and Disease ◽

10.1038/s41419-020-02960-6 ◽

2020 ◽

Vol 11 (9) ◽

Author(s):

Feiye Zhou ◽

Qianqian Liu ◽

Linlin Zhang ◽

Qin Zhu ◽

Shushu Wang ◽

...

Keyword(s):

Protein Degradation ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Selective Inhibition ◽

Chow Diet ◽

Creb Binding Protein ◽

Gene Expressions ◽

Primary Mouse

Abstract The histone acetyltransferases CREB-binding protein (CBP) and its paralogue p300 are transcriptional coactivators which are essential for a multitude of signaling pathways and energy homeostasis. However, the role of CBP/p300 HAT domain in regulating energy balance is still unclear. Here, C57BL/6 mice fed with either normal chow diet (NCD) or high-fat diet (HFD) were administrated with A-485, a recently reported selective inhibitor of CBP/p300 HAT activity for 1 week and the metabolic change was analyzed. The white adipose tissue (WAT) weight and adipocyte size were reduced in A-485-administrated mice, with decreased expressions of lipogenic genes and transcriptional factors. In the liver of A-485-treated mice, the lipid content and lipogenic gene expressions were lowered while the binding of forkhead box O1 (FOXO1) to glucose-6-phosphatase (G6Pc) promoter was reduced, leading to decreased expression of G6Pc. In primary mouse hepatocytes, A-485 abolished cAMP-elicited mRNA expressions of key gluconeogenic enzymes and promoted FOXO1 protein degradation via increasing its ubiquitination. Thus, A-485 inhibits lipogenesis in WAT and liver as well as decreases hepatic glucose production via preventing FOXO1 acetylation, leading to its protein degradation through a proteasome-dependent pathway. The specific inhibition of CBP/p300 HAT will provide a novel therapeutic approach for metabolic diseases.

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Influence of the presence of OB-Re on leptin radioimmunoassay

Journal of Endocrinology ◽

10.1677/joe.0.1680079 ◽

2001 ◽

Vol 168 (1) ◽

pp. 79-86 ◽

Cited By ~ 11

Author(s):

T Murakami ◽

S Otani ◽

T Honjoh ◽

T Doi ◽

K Shima

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Serum Levels ◽

Mouse Serum ◽

Serum Leptin ◽

Mouse Placenta ◽

Pregnant State

Leptin, a hormone derived from adipose tissue, regulates energy homeostasis and body weight. In the mouse, serum leptin levels, when measured by radioimmunoassay (RIA), increase by a factor of more than 50 times during pregnancy, compared with those in the non-pregnant state. It is well known that mouse placenta produces the secretory isoform of the leptin receptor, OB-Re. In order to investigate the issue of whether serum leptin levels are actually increased during pregnancy or whether the increased OB-Re concentration plays a role in this phenomenon, serum leptin levels were determined by the immunoprecipitation of leptin using anti-leptin antibody, and were found to be increased only by about ten times during pregnancy. To investigate the influence of OB-Re on leptin measurement by the RIA procedure, serum leptin levels were measured by the RIA after the addition of OB-Re to the serum. The apparent values of leptin levels increased in parallel with the amount of OB-Re added to the serum. Leptin levels, as determined by the RIA, might therefore provide artificially high values when serum levels of the secretory form of OB-R are high, in cases, for example, such as the last period of pregnancy in mice.

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Abstract 016: Bbs1 Gene Deletion From The Leptin Receptor Neurons Causes Obesity And Hypertension In Mice

Hypertension ◽

10.1161/hyp.64.suppl_1.016 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Deng F Guo ◽

Donald A Morgan ◽

Justin L Grobe ◽

Darryl Nishimura ◽

Charles Searby ◽

...

Keyword(s):

Body Weight ◽

Energy Expenditure ◽

Arterial Pressure ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Autosomal Recessive Disorder ◽

Obesity Phenotype ◽

Receptor Neurons ◽

Depressor Effect ◽

Old Mice

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive disorder associated with several features including obesity and hypertension. Deletion of BBS genes globally or in the nervous system recapitulated many of the BBS phenotypes including obesity and hypertension. Here, we assessed the effect of ablating the Bbs1 gene from the neurons expressing the long signaling form of the leptin receptor (LepRb). Breeding Bbs1 flox with LepRb Cre mice created mice deficient in the Bbs1 gene only in LepRb-positive neurons (visualized by tdTomato expression) as indicated by loss of leptin activation of Stat3. Importantly, Bbs1 flox /LepR Cre mice display an obesity phenotype as indicated by the increased (P<0.05) body weight (39±2 vs. 30±1 g in controls) and fat mass measured by MRI (14±3 vs. 4±1 g in controls) associated with increased (P<0.05) food intake (3.4±0.1 vs. 2.9±0.1 g in controls) in 25 weeks old mice. However, body weight and fat pads of pair-fed LRb Cre /Bbs1 fl/fl mice remained significantly elevated compared to controls suggesting that LRb Cre /Bbs1 fl/fl mice have reduced energy expenditure. Consistent with this possibility, LRb Cre /Bbs1 fl/fl mice displayed decreased (P<0.05) O 2 consumption (2.6±0.1 vs. 3.1±0.1 mL/100g/min in controls) and heat production (8.1±0.3 vs. 9.6±0.3 kcal/kg/h in controls). These results indicate that hyperphagia and decreased energy expenditure contribute to the development of obesity in Bbs1 flox /LepR Cre mice. Next, we assessed the effect on arterial pressure (AP) and sympathetic nerve activity (SNA) of ablating the Bbs1 gene from the LepR-containing neurons. Interestingly, deletion of the Bbs1 gene in LepR neurons recapitulates the hypertension phenotype of BBS as indicated by elevated mean AP (125±4 vs 109±3 mmHg in controls, P=0.03). Conscious renal SNA was also elevated in LRb Cre /Bbs1 fl/fl mice relative to controls (97±8 vs 62±10 spikes/sec, P<0.05). Finally, the depressor effect of ganglionic blockade (hexamethonium) was exaggerated in Bbs1 flox /LepR Cre mice (-57±5 vs -38±5 mmHg in control, P=0.01). These findings demonstrate that the Bbs1 gene in LepR neurons is critical for energy homeostasis and arterial pressure regulation.

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Abstract 198: Oral Administration of the Mas Agonist A-1317 Produces Beneficial Cardiometabolic Effects in Rats

Hypertension ◽

10.1161/hyp.62.suppl_1.a198 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Suellen F Vilas Boas ◽

Janaina F Braga ◽

Analina R Silva ◽

Mariana F Oliveira ◽

Robson A S Santos

Keyword(s):

Body Weight ◽

Glucose Tolerance ◽

Inclusion Compound ◽

Metabolic Diseases ◽

Spontaneously Hypertensive Rat ◽

Body Weight Gain ◽

The Body ◽

Oral Glucose ◽

Sprague Dawley ◽

Tissue Mass

The beneficial effects of the Mas/Ang-(1-7) pathway prompted us to develop novel Ang-(1-7) analogues and ligands for Mas. In the present study, we evaluated the cardiometabolic effects of a pharmacological formulation developed by including the Mas agonist A-1317 in hydroxypropyl β-cyclodextrin (HPβCD). The inclusion compound was given orally (10 μg/Kg body weight) to Spontaneously hypertensive rat (SHR) and fructose-fed rats. Mean arterial pressure (MAP) and heart rate (HR) were monitored for 5 hours after administration of a single dose of A-1317-HPβCD in conscious SHR. Seven-weeks-old male Sprague-Dawley rats were fed with either normal rat chow (CTL) or the same diet plus 10% fructose in the drinking water (FFR). For the last 4 wk of a 9-wk period of each diet, a subgroup of each group of animals was treated daily with the oral A-1317 (CTL-A or FFR-A) or with vehicle (CTL-V or FFR-V). Rats were subjected to oral glucose tolerance test (2 g/Kg body weight) concomitantly with the evaluation of plasma insulin levels. A-1317 reduced MAP with the maximum change occurring after 4 hours of administration (Δ=-23±2mmHg). There was no significant effect of A-1317 on HR of SHR. Once a day administration of A-1317 ameliorated all metabolic conditions altered by fructose-feed, including the glucose tolerance with less release of insulin and the decreased in the basal insulinemia. However no change in glycemia was observed. Regarding the lipidic metabolism, there was a decrease in the hepatic and serum tryacilglicerol levels (CTL-V=51±3; CTL-A=44±4; FFR-V=74±6; FFR-A=45±5 mg/dl serum levels), the body weight gain and the epididymal and mesenteric adipose tissue mass. Moreover hepatic and serum cholesterol levels were surprisingly diminished in both treated groups. These data suggest that A-1317 inclusion compound is an innovative therapeutic tool for treatment the cardiovascular and metabolic diseases.

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Lack of AR in LepRb Cells Disrupts Ambulatory Activity and Neuroendocrine Axes in a Sex-Specific Manner in Mice

Endocrinology ◽

10.1210/endocr/bqaa110 ◽

2020 ◽

Vol 161 (8) ◽

Author(s):

Alexandra L Cara ◽

Martin G Myers ◽

Carol F Elias

Keyword(s):

Energy Homeostasis ◽

Leptin Receptor ◽

Pubertal Timing ◽

Ambulatory Activity ◽

Estrous Cycles ◽

Female Mice ◽

Neuronal Populations ◽

Hypothalamic Nuclei ◽

Specific Manner ◽

Increase Risk

Abstract Disorders of androgen imbalance, such as hyperandrogenism in females or hypoandrogenism in males, increase risk of visceral adiposity, type 2 diabetes, and infertility. Androgens act upon androgen receptors (AR) which are expressed in many tissues. In the brain, AR are abundant in hypothalamic nuclei involved in regulation of reproduction and energy homeostasis, yet the role of androgens acting via AR in specific neuronal populations has not been fully elucidated. Leptin receptor (LepRb)–expressing neurons coexpress AR predominantly in hypothalamic arcuate and ventral premammillary nuclei (ARH and PMv, respectively), with low colocalization in other LepRb neuronal populations, and very low colocalization in the pituitary gland and gonads. Deletion of AR from LepRb-expressing cells (LepRbΔAR) has no effect on body weight, energy expenditure, and glucose homeostasis in male and female mice. However, LepRbΔAR female mice show increased body length later in life, whereas male LepRbΔAR mice show an increase in spontaneous ambulatory activity. LepRbΔAR mice display typical pubertal timing, estrous cycles, and fertility, but increased testosterone levels in males. Removal of sex steroid negative feedback action induced an exaggerated rise in luteinizing hormone in LepRbΔAR males and follicle-stimulating hormone in LepRbΔAR females. Our findings show that AR can directly affect a subset of ARH and PMv neurons in a sex-specific manner and demonstrate specific androgenic actions in the neuroendocrine hypothalamus.

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Central overexpression of leptin antagonist reduces wheel running and underscores importance of endogenous leptin receptor activity in energy homeostasis

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90449.2008 ◽

2009 ◽

Vol 297 (5) ◽

pp. R1254-R1261 ◽

Cited By ~ 15

Author(s):

Michael Matheny ◽

Yi Zhang ◽

Alexandra Shapiro ◽

Nihal Tümer ◽

Philip J. Scarpace

Keyword(s):

Body Weight ◽

Food Consumption ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Wheel Running ◽

Receptor Activity ◽

High Fat ◽

Fat Feeding ◽

Antagonist Group

We used recombinant adeno-associated virus (rAAV)-mediated gene delivery to overexpress a mutant of rat leptin yielding a protein that acts as a neutral leptin receptor antagonist. The long-term consequences of this overexpression on body weight homeostasis and physical activity, as assessed by voluntary wheel running (WR), were determined in F344 × Brown Norway (BN) rats. Leptin antagonist overexpression was confirmed by examination of mRNA levels in the hypothalamus. Food consumption and body weight gain were exacerbated in the antagonist group during both chow and high-fat feeding periods over the 192-day experiment. In a second experiment, a lower dose of antagonist vector was used that resulted in no change in food consumption but still increased body weight. The degree of antagonist overexpression was sufficient to partially block signal transducer and activator of transcription 3 (STAT3) phosphorylation due to administration of an acute submaximal dose of leptin. Rats were provided free access to running wheels for 4 days during both the chow and high-fat feeding periods. With both antagonist doses and during both chow and high-fat feeding, WR was substantially less with antagonist overexpression. In contrast, when leptin was overexpressed in the hypothalamus, WR activity was increased by greater than twofold. At death, adiposity and serum leptin levels were greater in the antagonist group. These data indicate that submaximal central leptin receptor blockade promotes obesity and diminishes WR activity. These findings underscore the critical role of unrestrained leptin receptor activity in long-term energy homeostasis and suggest that even minor disruption of leptin receptor function can promote obesity.

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Role of GABA Release From Leptin Receptor-Expressing Neurons in Body Weight Regulation

Endocrinology ◽

10.1210/en.2011-2071 ◽

2012 ◽

Vol 153 (5) ◽

pp. 2223-2233 ◽

Cited By ~ 36

Author(s):

Yuanzhong Xu ◽

William G. O'Brien ◽

Cheng-Chi Lee ◽

Martin G. Myers ◽

Qingchun Tong

Keyword(s):

Body Weight ◽

Food Intake ◽

Leptin Receptor ◽

Gaba Release ◽

Neuron Activity ◽

Chow Diet ◽

Weight Regulation ◽

Body Weight Regulation ◽

The Brain

It is well established that leptin regulates energy balance largely through isoform B leptin receptor-expressing neurons (LepR neurons) in the brain and that leptin activates one subset of LepR neurons (leptin-excited neurons) while inhibiting the other (leptin-inhibited neurons). However, the neurotransmitters released from LepR neurons that mediate leptin action in the brain are not well understood. Previous results demonstrate that leptin mainly acts on γ-aminobutyric acid (GABA)ergic neurons to reduce body weight, and that leptin activates proopiomelanocortin neuron activity by reducing GABA release onto these neurons, suggesting a body weight-promoting role for GABA released from leptin-inhibited neurons. To directly examine the role of GABA release from LepR neurons in body weight regulation, mice with disruption of GABA release specifically from LepR neurons were generated by deletion of vesicular GABA transporter in LepR neurons. Interestingly, these mice developed mild obesity on chow diet and were sensitive to diet-induced obesity, which were associated with higher food intake and lower energy expenditure. Moreover, these mice showed blunted responses in both food intake and body weight to acute leptin administration. These results demonstrate that GABA plays an important role in mediating leptin action. In combination with the previous studies that leptin reduces GABA release onto proopiomelanocortin neurons through leptin-inhibited neurons and that disruption of GABA release from agouti gene-related protein neurons, one subset of LepR-inhibited neurons, leads to a lean phenotype, our results suggest that, under our experimental conditions, GABA release from leptin-excited neuron dominates over leptin-inhibited ones.

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