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.

scholarly journals Tanycyte-independent control of hypothalamic leptin signaling

2019 ◽  
Author(s):  
Sooyeon Yoo ◽  
David Cha ◽  
Dong Won Kim ◽  
Thanh V. Hoang ◽  
Seth Blackshaw
Keyword(s):  
Gene Expression ◽  
Single Molecule ◽  
Leptin Receptor ◽  
Cell Types ◽  
Leptin Signaling ◽  
And Function ◽  
Induced Changes ◽  
The Brain ◽  
Specific Deletion

AbstractLeptin is secreted by adipocytes to regulate appetite and body weight. Recent studies have reported that tanycytes actively transport circulating leptin across the brain barrier into the hypothalamus, and are required for normal levels of hypothalamic leptin signaling. However, direct evidence for leptin receptor (LepR) expression is lacking, and the effect of tanycyte-specific deletion of LepR has not been investigated. In this study, we analyze the expression and function of the tanycytic LepR in mice. Using single-molecule fluorescent in situ hybridization (smfISH), RT-qPCR, single-cell RNA sequencing (scRNA-Seq), and selective deletion of the LepR in tanycytes, we are unable to detect expression of LepR in the tanycytes. Tanycyte-specific deletion of LepR likewise did not affect leptin-induced pSTAT3 expression in hypothalamic neurons, regardless of whether leptin was delivered by intraperitoneal or intracerebroventricular injection. Finally, we use activity-regulated scRNA-Seq (act-Seq) to comprehensively profile leptin-induced changes in gene expression in all cell types in mediobasal hypothalamus. Clear evidence for leptin signaling is only seen in endothelial cells and subsets of neurons, although virtually all cell types show leptin-induced changes in gene expression. We thus conclude that LepR expression in tanycytes is either absent or undetectably low, that tanycytes do not directly regulate hypothalamic leptin signaling through a LepR-dependent mechanism, and that leptin regulates gene expression in diverse hypothalamic cell types through both direct and indirect mechanisms.

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 MaMAPK3-MaICE1-MaPOD P7 pathway, a positive regulator of cold tolerance in banana

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jie Gao ◽  
Tongxin Dou ◽  
Weidi He ◽  
Ou Sheng ◽  
Fangcheng Bi ◽  
...  
Keyword(s):  
Transgenic Plants ◽  
Cold Tolerance ◽  
Molecular Breeding ◽  
Cold Resistance ◽  
Oxidoreductase Activity ◽  
Tropical Fruit ◽  
Over Expression ◽  
Cavendish Banana ◽  
Cold Tolerant ◽  
Necrotic Symptoms

Abstract Background Banana is a tropical fruit with a high economic impact worldwide. Cold stress greatly affects the development and production of banana. Results In the present study, we investigated the functions of MaMAPK3 and MaICE1 involved in cold tolerance of banana. The effect of RNAi of MaMAPK3 on Dajiao (Musa spp. ‘Dajiao’; ABB Group) cold tolerance was evaluated. The leaves of the MaMAPK3 RNAi transgenic plants showed wilting and severe necrotic symptoms, while the wide-type (WT) plants remained normal after cold exposure. RNAi of MaMAPK3 significantly changed the expressions of the cold-responsive genes, and the oxidoreductase activity was significantly changed in WT plants, while no changes in transgenic plants were observed. MaICE1 interacted with MaMAPK3, and the expression level of MaICE1 was significantly decreased in MaMAPK3 RNAi transgenic plants. Over-expression of MaICE1 in Cavendish banana (Musa spp. AAA group) indicated that the cold resistance of transgenic plants was superior to that of the WT plants. The POD P7 gene was significantly up-regulated in MaICE1-overexpressing transgenic plants compared with WT plants, and the POD P7 was proved to interact with MaICE1. Conclusions Taken together, our work provided new and solid evidence that MaMAPK3-MaICE1-MaPOD P7 pathway positively improved the cold tolerance in monocotyledon banana, shedding light on molecular breeding for the cold-tolerant banana or other agricultural species.

Loss of body fat in lean parabiotic partners of ob/ob mice

1997 ◽  
Vol 272 (6) ◽  
pp. R1809-R1815 ◽  
Author(s):  
R. B. Harris
Keyword(s):  
Food Intake ◽  
Mrna Expression ◽  
Body Fat ◽  
Rectal Temperature ◽  
Serum Insulin ◽  
Serum Leptin ◽  
Leptin Expression

The objective of this experiment was to confirm whether changes in serum leptin and leptin expression were consistent with it being the "lipostatic" factor implicated by earlier parabiosis studies. Lean (+/?) and obese (ob/ob) female C57B1/6J-ob mice were parabiosed (lean-ob/ob) at 7 wk of age. Controls were ob/ob-ob/ob and lean-lean pairs, and single lean and ob/ob mice. Pairs were maintained for 50 days. In ob/ob members of lean-ob/ob pairs serum insulin was normalized, food intake was suppressed, and body fat was reduced by 14%. Lean partners of ob/ob mice had a reduced rectal temperature and experienced a 37% reduction in body fat. Despite loss of fat, serum leptin and adipose leptin mRNA expression were unchanged in lean partners of ob/ob mice. These results suggest that, in lean-ob/ob parabiotic pairs, the ob/ob mouse responds to leptin originating in the lean parabiont, whereas the lean partner responds to a circulating signal, originating in the ob/ob mouse, that maintains leptin expression at inappropriate levels for the degree of adiposity of the lean animal.

Abstract 010: The Role of Angiotensin AT 1A Receptors in Leptin-sensitive Cells in Resting Metabolic Rate Control

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Kristin E Claflin ◽  
Justin L Grobe
Keyword(s):  
Metabolic Rate ◽  
Rate Control ◽  
Leptin Receptor ◽  
Resting Metabolic Rate ◽  
Critical Role ◽  
Renin Angiotensin System ◽  
Chow Diet ◽  
Brown Adipose ◽  
Diet Induced Thermogenesis ◽  
The Brain

The brain renin-angiotensin system (RAS) and leptin contribute to the control of resting metabolic rate (RMR) and their receptors are co-expressed in areas of the brain critical for metabolic control; thus angiotensin and leptin may interact within the brain to regulate RMR and obesity. Inhibition of the brain RAS attenuates sympathetic nerve activity (SNA) responses to leptin, leading us to hypothesize that the brain RAS mediates the RMR effects of leptin. Mice lacking angiotensin AT 1A receptors in leptin receptor-expressing cells (ObRb-Cre x AT 1A flox/flox ; “KO”) exhibited normal body weight (15 weeks of age: control n=28, 26.0 ± 0.7, vs KO n=35, 25.8 ± 0.6 g), food intake (control n=12, 3.1 ± 0.15, vs KO n=15, 3.4 ± 0.14 g) and RMR (control n=13, 0.15 ± 0.004, vs KO n=15, 0.16 ± 0.006 kcal/hr) on standard chow diet. Brown adipose SNA responses to acute leptin injection, however, were completely attenuated in KO mice. When maintained on a 45% high fat diet (HFD), KO mice gained significantly more fat mass (control n=35, 5.6 ± 0.4, vs KO n=31, 7.4 ± 0.5 g, P<0.05) and body mass (control, 27.4 ± 0.6, vs KO, 29.6 ± 0.6 g, P<0.05) due to a loss of diet-induced thermogenesis (control n=22, 0.18 ± 0.008, vs. KO n=12, 0.16 ± 0.004 kcal/hr, P<0.05). KO mice exhibited attenuated hypothalamic proopiomelanocortin (POMC) gene expression and partially attenuated RMR responses to alpha-melanocyte stimulating hormone (αMSH; control n=3, 0.25 ± 0.01, vs KO n=7, 0.2 ± 0.01 kcal/hr, P<0.05) indicating that the interaction between leptin and AT 1A modulates both αMSH production and action. To localize the site of the brain RAS-leptin interaction, we developed novel multi-transgenic mouse models which expresses GFP via the AT 1A promoter (NZ44, from GenSat) and/or conditional activation of a tdTomato reporter (ROSA-stop flox -tdTomato) in cells expressing the leptin receptor (ObRb-Cre) or agouti-related peptide (AgRP-Cre). Immunohistochemical staining of adrenocorticotropin in brain tissue from NZ44 mice revealed no localization of AT 1A to POMC neurons; in contrast, AT 1A was strongly localized with AgRP promoter activity. Taken together, these data support a critical role for angiotensin AT 1A receptors on AgRP neurons in the arcuate nucleus in resting metabolic rate control.

scholarly journals Effect of breakfast fat content on glucose tolerance and risk factors of atherosclerosis and thrombosis

1998 ◽  
Vol 80 (4) ◽  
pp. 323-331 ◽  
Author(s):  
David L. Frape ◽  
Norman R. Williams ◽  
Jayshri Rajput-Williams ◽  
B. W. Maitland ◽  
A. J. Scriven ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Thrombus Formation ◽  
Serum Insulin ◽  
Lipid Fraction ◽  
Tolerance Test ◽  
Serum Glucose ◽  
Oral Glucose ◽  
Significant Treatment ◽  
Treatment Allocation ◽  
Insulin Responses

Twenty-four middle-aged healthy men were given a low-fat high-carbohydrate (5.5 g fat; L), or a moderately-fatty, (25.7 g fat; M) breakfast of similar energy contents for 28 d. Other meals were under less control. An oral glucose tolerance test (OGTT) was given at 09.00 hours on day 1 before treatment allocation and at 13.30 hours on day 29. There were no significant treatment differences in fasting serum values, either on day 1 or at the termination of treatments on day 29. The following was observed on day 29: (1) the M breakfast led to higher OGTT C-peptide responses and higher areas under the curves (AUC) of OGTT serum glucose and insulin responses compared with the OGTT responses to the L breakfast (P< 0.05); (2) treatment M failed to prevent OGTT glycosuria, eliminated with treatment L; (3) serum non-esterified fatty acid (NEFA) AUC was 59% lower with treatment L than with treatment M, between 09.00 and 13.20 hours (P<0.0001), and lower with treatment L than with treatment M during the OGTT (P= 0.005); (4) serum triacylglycerol (TAG) concentrations were similar for both treatments, especially during the morning, but their origins were different during the afternoon OGTT when the Svedberg flotation unit 20–400 lipid fraction was higher with treatment L than with treatment M (P= 0.016); plasma apolipoprotein B-48 level with treatment M was not significantly greater than that with treatment L (P= 0.086); (5) plasma tissue plasminogen-activator activity increased after breakfast with treatment L (P= 0.0008), but not with treatment M (P= 0.80). Waist:hip circumference was positively correlated with serum insulin and glucose AUC and with fasting LDL-cholesterol. Waist:hip circumference and serum TAG and insulin AUC were correlated with factors of thrombus formation; and the OGTT NEFA and glucose AUC were correlated. A small difference in fat intake at breakfast has a large influence on circulating diurnal NEFA concentration, which it is concluded influences adversely glucose tolerance up to 6 h later.

scholarly journals Testosterone substitution of hypogonadal men prevents the age-dependent increases in body mass index, body fat and leptin seen in healthy ageing men: results of a cross-sectional study

2002 ◽  
pp. 505-511 ◽  
Author(s):  
C Rolf ◽  
S von Eckardstein ◽  
U Koken ◽  
E Nieschlag
Keyword(s):  
Fat Mass ◽  
Serum Testosterone ◽  
Cross Sectional Study ◽  
Fat Content ◽  
Sectional Study ◽  
Cross Sectional ◽  
Serum Leptin ◽  
Testosterone Substitution ◽  
Age Dependent ◽  
Total Fat

INTRODUCTION: In healthy men, body weight and total fat content increase with advancing age, while serum testosterone levels decrease. In order to elucidate whether a causal relationship between these phenomena exists, we investigated the influence of testosterone or human chorionic gonadotrophin substitution on body mass index (BMI), total fat mass and serum leptin in testosterone-treated and untreated hypogonadal patients in comparison with ageing eugonadal men. METHODS: In a cross-sectional study, the inter-relationships of body weight, total fat mass, serum sex hormones and leptin were analysed in untreated hypogonadal men (n=24; age 19-65 years), treated hypogonadal men (n=61; age 20-67 years) and healthy eugonadal men (n=60; age 24-78 years). Total fat mass was assessed by bioimpedance measurement. Univariate and multiple linear regression analysis was used to detect possible differences. RESULTS: In eugonadal men, serum testosterone levels decreased with advancing age (correlation coefficients: r=-0.71; P<0.0001), while BMI (r=0.39; P=0.002), total fat content (r=0.51; P<0.0001) and leptin (r=0.48; P<0.0001) increased significantly. In untreated hypogonadal patients, an increase in BMI (r=0.50; P=0.013) and total fat mass (r=0.41; P=0.044) was also observed with advancing age. However, in substituted hypogonadal patients, no age-dependent change in BMI (r=0.067; P=0.606), body fat content (r=-0.083; P=0.522), serum testosterone (r=-0,071; P=0.59) or serum leptin (r=-0.23; P=0.176) was found. CONCLUSION: Since testosterone-substituted older hypogonadal men show BMI and fat mass similar to those of younger eugonadal men and since non-treated hypogonadal men are similar to normal ageing men, testosterone appears to be an important factor contributing to these changes. Thus ageing men should benefit from testosterone substitution as far as body composition is concerned.

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