Abstract 25: Angiotensin AT 1A Receptors on Leptin Receptor-Expressing Cells are Required for the Blood Pressure and Metabolic Rate Effects of Leptin

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Justin L Grobe ◽  
Kristin E Claflin
Keyword(s):  
Blood Pressure ◽  
Metabolic Rate ◽  
Body Mass ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Brain Regions ◽  
Leptin Resistance ◽  
Brown Adipose ◽  
Obesity Hypertension ◽  
The Brain

Circulating leptin and the local brain renin-angiotensin system (RAS) both contribute to the control of food intake (FI), resting metabolic rate (RMR) and blood pressure (BP), and both have been postulated to contribute to obesity-hypertension. Here we examined the provocative hypothesis that the brain RAS is required for (or mediates) the RMR- and BP-stimulating effects of leptin. To create animals lacking the AT 1A receptor specifically in cells expressing the leptin receptor (“KO”), mice with a flox’ed version of the endogenous angiotensin AT 1A receptor gene (AT 1A flox ) were crossed with mice expressing cre-recombinase via the leptin receptor promoter (ObR-Cre). Body mass, body composition, blood chemistry, glucose tolerance, and FI behaviors were essentially unchanged through 34 weeks of age in mice maintained on standard chow (Teklad 7013). In contrast, anesthetized BP (MAP; control n=9, 91.6 ± 4.1, vs KO n=8, 78.0 ± 3.7 mmHg) and heart rate (351 ± 13, vs 308 ± 11 BPM) were reduced in KO mice (both P<0.05). Further, interscapular brown adipose (BAT SNA, 112 ± 22, vs 22 ± 35 % above baseline at 3 hr) and renal (154 ± 19, vs 53 ± 23 % above baseline at 3 hr) sympathetic nerve activity responses to acute leptin injection (60 μg, i.v.) were completely abolished (both P<0.05). When maintained on a 45% high fat diet (OpenSource D12451 ) to increase endogenous leptin production, KO mice exhibited accelerated body mass (control n=15, -0.1 ± 0.1, vs KO n=4, +1.7 ± 0.5 g/wk) and fat mass (+2.9 ± 0.5, vs +4.9 ± 1.1 g/5 wk) gains (both P<0.05), likely due to normal FI behaviors but a 18% reduction in RMR (control n=16, 0.196 ± 0.011, vs KO n=7, 0.161 ± 0.004 kcal/hr at 30°C, P<0.05). We conclude that expression of angiotensin AT 1A receptors on leptin-sensitive cells is required for the metabolic rate and cardiovascular effects of leptin. Ongoing studies are focused on identifying the brain regions and subsets of leptin receptor-expressing cells in which this RAS-leptin cross-talk occurs, and the directionality and molecular mediators of this interaction. We hypothesize that uncontrolled or pathological activity of the brain RAS may thus help explain the clinically variable effects of leptin, and contribute to the mechanism(s) of selective leptin resistance and obesity-hypertension.

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.

Fever responses of Zucker rats with and withoutfatty mutation of the leptin receptor

2002 ◽  
Vol 282 (1) ◽  
pp. R311-R316 ◽  
Author(s):  
Andrei I. Ivanov ◽  
Andrej A. Romanovsky
Keyword(s):  
Leptin Receptor ◽  
Receptor Gene ◽  
Zucker Rats ◽  
Saline Stress ◽  
Brown Adipose ◽  
Cool Environment ◽  
Obese Rats ◽  
Colonic Temperature ◽  
The Brain ◽  
Escherichia Coli Lipopolysaccharide

Leptin is thought to be involved in febrigenic signaling from the periphery to the brain. Zucker obese rats have a so-called fatty mutation in the leptin receptor gene and express a dysfunctional protein. Studies comparing the fever responses of fatty ( fa/fa) rats and of their lean ( Fa/Fa and Fa/fa) counterparts yield contradictory results. To resolve these contradictions, we evaluated the effect of fatty mutation on infectious and stress-associated fevers at thermoneutrality (29°C) and in a cool environment (20°C). Zucker fa/fa and Fa/? rats were infused with Escherichia coli lipopolysaccharide (LPS; 10 μg/kg) through a jugular catheter (infectious fever) or with saline through the catheter (control) or received a painful intramuscular injection of saline (stress fever). At thermoneutrality, the colonic temperature (Tc) responses of fattyrats to all stimuli tested were no different from the responses of lean rats. In a cool environment, Tc responses of fatty rats to all stimuli were ∼0.5°C lower than those of lean rats. The observed attenuation of LPS-induced and stress-associated fevers in Zucker fatty rats in the cold agrees with the literature data showing that brown adipose tissue (the major heat production effector) is morphologically and functionally defective in these rats. The normal febrile responses of fatty Zucker rats to pyrogenic stimuli at thermoneutrality indicate that fatty mutation does not interrupt febrigenic signaling from the periphery to the brain.

scholarly journals Physiological leptin resistance

2016 ◽  
Vol 72 (10) ◽  
pp. 604-610
Author(s):  
Patrycja Gogga ◽  
Joanna Karbowska ◽  
Włodzimierz Meissner ◽  
Zdzisław Kochan
Keyword(s):  
Body Fat ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Leptin Resistance ◽  
Main Function ◽  
Fat Reserves ◽  
Energy Needs ◽  
Fat Stores ◽  
The Brain ◽  
Regulate Energy Metabolism

Leptin is an adipose tissue-derived hormone whose circulating levels correlate with the amount of body fat stores. The main function of this adipokine is to regulate energy metabolism. By modulating the expression of orexigenic and anorexigenic neuropeptides in the hypothalamus, leptin reduces appetite. It also increases energy expenditure, contributing to the decrease of body fat and body weight. Mutations in the leptin receptor gene or prolonged consumption of a high-fat diet may impair leptin action, leading to leptin resistance. Resistance to leptin can also be an adaptive response that occurs in seasonal animals and in pregnant mammals. Reversible insensitivity to the satiety signal of leptin promotes hyperphagia, which is essential for animals living in dynamic environments and experiencing seasonal variation in food availability, since it allows them to forage intensely when food is abundant and accumulate fat reserves necessary to survive periods when food is scarce. Moreover, leptin resistance and subsequent hyperphagia develop during pregnancy in order to meet the energy needs of the growing fetus. Physiological leptin resistance may be due to impaired transport of leptin across the blood-brain barrier and/or to decreased sensitivity of the hypothalamus to this hormone resulting from an inhibition of leptin signalling in hypothalamic neurons. In pregnancy, an increased resistance to leptin action is also mediated by the binding of this adipokine to its placenta-derived soluble receptor. Reduced entry of leptin into the brain as well as alterations in the leptin signalling pathway in the hypothalamus leads to a transient decrease in sensitivity to this hormone preventing appetite suppression.

Sex, the brain and hypertension: brain oestrogen receptors and high blood pressure risk factors

2015 ◽  
Vol 130 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Meredith Hay
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Older Women ◽  
Premenopausal Women ◽  
Brain Regions ◽  
Oestrogen Receptors ◽  
The Common ◽  
Key Sites ◽  
The Brain ◽  
Underlying Risk

Hypertension is a major contributor to worldwide morbidity and mortality rates related to cardiovascular disease. There are important sex differences in the onset and rate of hypertension in humans. Compared with age-matched men, premenopausal women are less likely to develop hypertension. However, after age 60, the incidence of hypertension increases in women and even surpasses that seen in older men. It is thought that changes in levels of circulating ovarian hormones as women age may be involved in the increase in hypertension in older women. One of the key mechanisms involved in the development of hypertension in both men and women is an increase in sympathetic nerve activity (SNA). Brain regions important for the regulation of SNA, such as the subfornical organ, the paraventricular nucleus and the rostral ventral lateral medulla, also express specific subtypes of oestrogen receptors. Each of these brain regions has also been implicated in mechanisms underlying risk factors for hypertension such as obesity, stress and inflammation. The present review brings together evidence that links actions of oestrogen at these receptors to modulate some of the common brain mechanisms involved in the ability of hypertensive risk factors to increase SNA and blood pressure. Understanding the mechanisms by which oestrogen acts at key sites in the brain for the regulation of SNA is important for the development of novel, sex-specific therapies for treating hypertension.

Maternal obesity increases hypothalamic leptin receptor expression and sensitivity in juvenile obesity-prone rats

2007 ◽  
Vol 292 (5) ◽  
pp. R1782-R1791 ◽  
Author(s):  
Judith N. Gorski ◽  
Ambrose A. Dunn-Meynell ◽  
Barry E. Levin
Keyword(s):  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Maternal Obesity ◽  
Subsequent Development ◽  
Receptor Expression ◽  
Leptin Resistance ◽  
Melanocortin 4 Receptor ◽  
Time Period ◽  
Brown Adipose ◽  
Juvenile Obesity

In rats selectively bred to develop diet-induced obesity (DIO) or to be diet-resistant (DR), DIO maternal obesity selectively enhances the development of obesity and insulin resistance in their adult offspring. We postulated that the interaction between genetic predisposition and factors in the maternal environment alter the development of hypothalamic peptide systems involved in energy homeostasis regulation. Maternal obesity in the current studies led to increased body and fat pad weights and higher leptin and insulin levels in postnatal day 16 offspring of both DIO and DR dams. However, by 6 wk of age, most of these intergroup differences disappeared and offspring of obese DIO dams had unexpected increases in arcuate nucleus leptin receptor mRNA, peripheral insulin sensitivity, diet- and leptin-induced brown adipose temperature increase and 24-h anorectic response compared with offspring of lean DIO, but not lean DR dams. On the other hand, while offspring of obese DIO dams did have the highest ventromedial nucleus melanocortin-4 receptor expression, their anorectic and brown adipose thermogenic responses to the melanocortin agonist, Melanotan II (MTII), did not differ from those of offspring of lean DR or DIO dams. Thus, during their rapid growth phase, juvenile offspring of obese DIO dams have alterations in their hypothalamic systems regulating energy homeostasis, which ameliorates their genetic and perinatally determined predisposition toward leptin resistance. Because they later go onto become more obese, it is possible that interventions during this time period might prevent the subsequent development of obesity.

scholarly journals Genetic aspects of metabolic disorders in pregnant women with pathological weight gain

2019 ◽  
Vol 10 (3) ◽  
pp. 271-275
Author(s):  
S. O. Ostafiichuk
Keyword(s):  
Weight Gain ◽  
Pregnant Women ◽  
Leptin Receptor ◽  
Metabolic Diseases ◽  
Receptor Gene ◽  
Insulin Level ◽  
Late Pregnancy ◽  
Serum Levels ◽  
Leptin Resistance ◽  
Enzyme Linked Immunosorbent Assay

Polymorphism of the leptin receptor gene (LEPR) has been shown to be linked to obesity-related metabolic markers and phenotype. Therefore, we hypothesized that the Gln233Arg LEPR polymorphism is related to metabolic changes in pregnancy and the risk of excessive gestational weight gain (GWG). A total of 97 pregnant women with a singleton gestation were enrolled from April 2016 until December 2018. Genetic variants of LEPR were analyzed by real-time polymerase chain reaction, leptin by enzyme-linked immunosorbent assay, lipid profile, and carbohydrate status were assessed in the first, and third trimesters of pregnancy. The recommended GWG was diagnosed in 34.0%, insufficient in 19.6%, and excessive in 46.4% patients. Statistical analysis revealed that 20.6% patients were with AA genotype, 50.5% – AG genotype, and 28.9% – GG genotype. The frequency of GG-alleles carriers of the LEPR Gln233Arg gene in the group of excessive GWG patients was 3 times higher compared to recommended GWG patients. Thus, the inheritance of pathological G-homozygotes increases the risk of excessive weight gain by 7 times, compared to carriers of the AA genotype. LEPR GG polymorphism was significantly associated with high levels of triglycerides, total cholesterol, lipoprotein low and very low density, and leptin compared to homozygous А-carriers in the third trimester of pregnancy. In pregnant women with GG polymorphism, the glucose level, insulin level, and HOMO-IR index were significantly increased compared to women with AA genotype in late pregnancy. In the group with excessive GWG, the presence of GG-alleles of the LEPR gene was accompanied by a higher level of hyperleptinemia, compared to carriers of AA-genotype. Inheritance of pathological G-homozygotes was associated with hyperlipidemia, leptin resistance with high leptin serum levels, and increased insulin resistance, which was especially manifested in excessive GWG. In our opinion, excessive GWG can be seen as a marker of the mother's genotype and genetic predisposition to the development of metabolic diseases after delivery.

scholarly journals Alteration of the Leptin Network in Late Morbid Obesity Induced in Mice by Brain Infection with Canine Distemper Virus

1999 ◽  
Vol 73 (9) ◽  
pp. 7317-7327 ◽  
Author(s):  
Arlette Bernard ◽  
Richard Cohen ◽  
Seng-Thuon Khuth ◽  
Bruno Vedrine ◽  
Olivier Verlaeten ◽  
...  
Keyword(s):  
Canine Distemper Virus ◽  
Leptin Receptor ◽  
Motor Impairment ◽  
Brain Structures ◽  
Receptor Expression ◽  
Leptin Resistance ◽  
Obese Mice ◽  
Canine Distemper ◽  
New Paradigm ◽  
The Brain

ABSTRACT Viruses can induce progressive neurologic disorders associated with diverse pathological manifestations, and therefore, viral infection of the brain can impair differentiated neural functions, depending on the initial viral tropism. We have previously reported that canine distemper virus (CDV) targets certain mouse brain structures, including the hypothalamus, early and selectively. Infected mice exhibit acute encephalitis, with late disease, characterized by motor impairment or obesity syndrome, appearing in some of the surviving mice several months after the initial viral replication. In the present study, we show viral persistence in the hypothalami of obese mice, as demonstrated by low, but still significant, levels of CDV nucleoprotein transcripts, associated with a dramatic decrease in F gene mRNAs. Given the pivotal role of the hypothalamus in obesity (eating behavior, energy consumption, and neuroendocrine function) and that of leptin, the adipose tissue-derived satiety factor acting through hypothalamic receptors, we analyzed the leptin networks in both obese and nonobese mice. The discrepancy found between the chronic and dramatic increase in blood leptin levels and the occurrence of obesity may be due to leptin resistance in the brain. In fact, expression of the long leptin receptor isoform, representing the functional leptin receptor, was specifically downregulated in the hypothalami of obese mice, explaining their inability to generate an adequate response to leptin in the brain. Intriguingly, during the acute phase of infection, its expression was increased in CDV-targeted structures in all infected mice and remained high in obese mice in all CDV-targeted structures, except for the hypothalamus. The biphasic change in hypothalamic leptin receptor expression seen during the progression of CDV-induced obesity provides a new paradigm for understanding mechanisms of neuroendocrinological, virus-induced abnormalities.

scholarly journals The Relationship Between Modified Nordic Diet and Resting Metabolic Rate Among Overweight and Obese Participants: A Cross Sectional Study

2020 ◽  
Author(s):  
Ghazaleh Khalili ◽  
Atieh Mirzababaei ◽  
Farideh Shiraseb ◽  
Khadijeh Mirzaei
Keyword(s):  
Blood Pressure ◽  
Body Mass Index ◽  
Metabolic Rate ◽  
Body Mass ◽  
Resting Metabolic Rate ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Cross Sectional ◽  
Lower Odds ◽  
Nordic Diet

Abstract Objective: Obesity as a worldwide phenomenon is a multifactorial condition. Healthy diets have effect on obesity related factors like resting metabolic rate (RMR). In present study, we investigate association between adherence to modified Nordic diet and RMR among overweight and obese participants.Methods: We enrolled 404 overweight and obese (BMI ≥25 kg/m2) women aged 18-48 years in this cross-sectional study. For each participant anthropometrics measurements, biochemical tests and blood pressure were evaluated. RMR was measured by indirect calorimetry. RMR/kg was also measured. Modified Nordic diet score was measured using a validated 147-item food frequency questionnaire (FFQ).Results: Among all participants, the mean and standard deviation (SD) for age and body mass index (BMI) were 36.67 years (SD=9.10) and 31.26 kg/m2 (SD=4.29). There was a significant association between RMR/kg status and age, body mass index (BMI), RMR (P<0.001), respiratory quotient (RQ), fat percentage (P= 0.01), systolic blood pressure (SBP) (P= 0.03), and diastolic blood pressure (DBP) (P= 0.04), after adjustment for age, BMI, energy intake and physical activity. Participants with the highest adherence to modified Nordic diet had lower odds of hypometabolic status after adjusting for confounders and it was significant (odds ratio (OR) = 3.15, 95% CI= 0.97-10.15, P=0.05).Conclusions: The present results indicate that adherence to modified Nordic diet is associated with lower odds of hypometabolic status in overweight and obese women. However more studies are needed to confirm our findings.

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