Microcirculatory and glycocalyx properties are lowered by high salt diet but augmented by western diet in genetically heterogeneous mice

2022 ◽  
Author(s):  
Xiangyu Zheng ◽  
Christina Deacon ◽  
Abigail J King ◽  
Daniel R Machin
Keyword(s):  
Barrier Function ◽  
Boundary Region ◽  
Microvascular Density ◽  
Western Diet ◽  
High Salt ◽  
Chow Diet ◽  
Male And Female ◽  
Female Mice ◽  
Normal Chow ◽  
Analysis System

Many individuals in industrialized societies consume a high salt, western diet, however, the effects of this diet on microcirculatory properties and glycocalyx barrier function are unknown. Young genetically heterogeneous male and female mice underwent 12 weeks of normal chow diet (NC), NC diet with 4% salt (NC4%), western diet (WD), or WD with 4% salt (WD4%). Microcirculatory properties and glycocalyx barrier function were evaluated in the mesenteric microcirculation using an intravital microscope equipped with an automated capture and analysis system. Total microvascular density summed across 4-25 μm microvessel segment diameters was lower in NC4% compared to NC and WD (P<0.05). Perfused boundary region (PBR), a marker of glycocalyx barrier function, averaged across 4-25 μm microvessel segment diameters was similar between NC and NC4%, as well as between WD and WD4% (P>0.05). PBR was lower in WD and WD4% compared to NC and NC4% (P<0.05), indicating augmented glycocalyx barrier function in WD and WD4%. There were strong, inverse relationships between PBR and adiposity and blood glucose (r=-0.44 to -0.61, P<0.05). In summary, NC4% induces deleterious effects on microvascular density, whereas WD augments glycocalyx barrier function. Interestingly, the combination of high salt, western diet in WD4% resulted in lower total microvascular density like NC4% and augmented glycocalyx barrier function like WD. These data suggest distinct microcirculatory adaptations to high salt and western diets that coincide when these diets are combined in young genetically heterogeneous male and female mice.

scholarly journals Advanced age results in a diminished endothelial glycocalyx

2018 ◽  
Vol 315 (3) ◽  
pp. H531-H539 ◽  
Author(s):  
Daniel R. Machin ◽  
Samuel I. Bloom ◽  
Robert A. Campbell ◽  
Tam T. T. Phuong ◽  
Phillip E. Gates ◽  
...  
Keyword(s):  
Intravital Microscopy ◽  
Barrier Function ◽  
Microvascular Dysfunction ◽  
Boundary Region ◽  
Microvascular Density ◽  
Advanced Age ◽  
Endothelial Glycocalyx ◽  
Age Related ◽  
Analysis System ◽  
Glycocalyx Thickness

Age-related microvascular dysfunction is well characterized in rodents and humans, but little is known about the properties of the microvascular endothelial glycocalyx in advanced age. We examined the glycocalyx in microvessels of young and old male C57BL6 mice (young: 6.1 ± 0.1 mo vs. old: 24.6 ± 0.2 mo) using intravital microscopy and transmission electron microscopy and in human participants (young: 29 ± 1 yr vs. old: 60 ± 2 yr) using intravital microscopy. Glycocalyx thickness in mesenteric and skeletal muscle microvessels was 51–54% lower in old compared with young mice. We also observed 33% lower glycocalyx thickness in the sublingual microcirculation of humans in advanced age. The perfused boundary region, a marker of glycocalyx barrier function, was also obtained using an automated capture and analysis system. In advanced age, we observed a 10–22% greater perfused boundary region in mice and humans, indicating a more penetrable glycocalyx. Finally, using this automated analysis system, we examined perfused microvascular density and red blood cell (RBC) fraction. Perfused microvascular density is a marker of microvascular function that reflects the length of perfused microvessel segments in a given area; RBC fraction represents the heterogeneity in RBC presence between microvessel segments. Compared with young, the perfused microvascular density was 16–21% lower and RBC fraction was 5–14% lower in older mice and in older humans. These data provide novel evidence that, across mammalian species, a diminished glycocalyx is present in advanced age and is accompanied by markers of impaired microvascular perfusion. Age-related glycocalyx deterioration may be an important contributor to microvascular dysfunction in older adults and subsequent pathophysiology. NEW & NOTEWORTHY Advanced age is characterized by microvascular dysfunction that contributes to age-related cardiovascular diseases, but little is known about endothelial glycocalyx properties in advanced age. This study reveals, for the first time, lower glycocalyx thickness and barrier function that is accompanied by impaired microvascular perfusion in both mice and humans in advanced age.

The Anti-Thrombotic Enzyme ADAMTS13 Reduces Inflammation and the Development of Atherosclerosis In Mice

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 367-367
Author(s):  
Anil K Chauhan ◽  
Chintan Gandhi ◽  
Mohammad Moshahid Khan ◽  
Steven R. Lentz
Keyword(s):  
Carotid Sinus ◽  
Plaque Formation ◽  
Western Diet ◽  
Chow Diet ◽  
High Fat ◽  
Lesion Area ◽  
Aortic Sinus ◽  
Male And Female ◽  
Atherosclerotic Plaque Formation ◽  
Normal Chow

Abstract Abstract 367 Background and objective: ADAMTS13 (A Disintegrin-like And Metalloprotease with Thrombospondin type I repeats-13) plays a pivotal role in preventing spontaneous thrombosis in the microvasculature by cleaving hyperactive ultra large von Willebrand factor (ULVWF) multimers into smaller, less active multimers. Severe deficiency of ADAMTS13 in humans causes thrombotic thrombocytopenic purpura (TTP) and numerous epidemiological studies have demonstrated associations between decreased ADAMTS13 activity and adverse disease outcome in patients with systemic inflammation. It remains unknown, however, whether reduced ADAMTS13 activity plays a direct pathogenic role in inflammatory diseases or rather simply serves as an inflammation-associated marker. We hypothesized that deficiency of ADAMTS13 enhances inflammation and accelerates the development of early atherosclerotic plaques. Results: Using intravital fluorescence microscopy, we show that the number of adherent leukocytes (adherent for > 60 s) was increased approximately four-fold at the carotid sinus, a lesion prone site, of Adamts13−/−/ApoE−/− mice (Mean ± SEM = 37 ± 6) as compared to ApoE−/− mice (Mean ± SEM = 9 ± 4, P <0.01) fed a high-fat Western diet. Interestingly, intravital microscopy showed that 100% (10/10) of the Adamts13−/−/ApoE−/− mice had plaque that occluded the carotid sinus by approximately 70–80%, whereas only 20% (2/10) of the ApoE−/− mice had plaque at the carotid sinus, and the plaques were smaller in size than those in Adamts13−/−/ApoE−/− mice (P=0.0003). Next, we determined the effects of ADAMTS13 deficiency on atherosclerotic plaque formation in the aorta and aortic sinus. We compared the extent of atherosclerosis in whole aortae stained with Oil Red O and en face lesion area measured by morphometry. Both Adamts13−/−/ApoE−/− male and female mice demonstrated significantly larger lesions in the descending aorta (P<0.01), arch of the aorta (P<0.001), and total aorta (P<0.0001) compared to ApoE−/− mice fed a high-fat Western diet. Next, we quantified the corss-sectional area of lesions in the aortic sinus using the VerHoeffs/Van Gieson method. We observed a two-fold increase in the mean lesion area in the aortic sinus of both male and female Adamts13−/−/ApoE−/− mice (P<0.01) compared to ApoE−/− mice. Macrophage content (% of total lesion area), as quantitated by immunohistochemistry, was significantly elevated in the aortic root lesions of Adamts13−/−/ApoE−/− mice compared to ApoE−/− mice, suggesting that exacerbated atherosclerosis was due to increased inflammation. Adamts13−/−/ApoE−/− mice fed a normal chow diet also demonstrated accelerated atherosclerotic plaque formation compared to ApoE−/− mice. Total cholesterol and triglyceride levels were similar in Adamts13−/−/ApoE−/− and ApoE−/− mice fed a high-fat Western diet or normal chow diet. Conclusions: These findings unravel a new functional role for the anti-thrombotic enzyme ADAMTS13 in reducing excessive inflammation and plaque formation during atherosclerosis. Disclosures: Lentz: Celgene: Ownership interest; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 096: Leptin and High Salt Diet Induce Greater Increases in Blood Pressure in Female than Male Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Jessica L Faulkner ◽  
Eric J Belin de Chantemele
Keyword(s):  
Blood Pressure ◽  
Recovery Period ◽  
Pressure Rise ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Male And Female ◽  
Female Mice ◽  
Males And Females ◽  
Blood Pressure Responses

Recent studies by our group demonstrated that leptin is a direct regulator of aldosterone secretion and increases blood pressure via sex-specific mechanisms involving leptin-mediated activation of the aldosterone-mineralocorticoid receptor signaling pathway in females and sympatho-activation in males. Although it is well accepted that females secrete more leptin and aldosterone than males, it is unknown whether leptin infusion raises blood pressure similarly in male and female mice and whether higher aldosterone levels sensitize females to salt-induced hypertension. We hypothesized that female mice would be more sensitive to leptin than males and also have a potentiated blood pressure rise in response to high salt diet compared to males. Male and female Balb/C mice were implanted with radiotelemeters for continuous measurement of mean arterial pressure (MAP) at 10 weeks of age. MAP was measured for seven days prior to feeding with a high-salt diet (HS, 4%NaCl) for seven days. Following a recovery period, animals were then implanted with osmotic minipumps containing leptin (0.9mg/kg/day) recorded for seven days. Baseline MAP was similar between males and females (101.3±2.9 vs 99.3±3.7 mmHg, n=4 and 5, respectively), however, HS diet resulted in a greater MAP increase in females (15.0±2.6 mmHg) compared to males (3.1±4.5 mmHg, P<0.05). MAP with leptin treatment was increased with leptin in females moreso than in males, however, this did not reach significance (6.8±5.8 vs 1.8±5.9 mmHg, respectively). This potential sex difference in blood pressure responses to leptin was not associated with changes in body weight (0.07±0.44 vs -0.22±0.2 g, respectively) nor changes in blood glucose (-19.67±15.06 vs -15.4±11.4 mg/dl, respectively) in males and females in response to leptin. In summary, female mice are more sensitive to HS diet-induced blood pressure increases than males. Females may be more sensitive to leptin-mediated blood pressure increases than males. Further investigation is needed to determine whether these sex differences in blood pressure responses to HS diet and leptin are mediated by aldosterone or other mechanisms.

scholarly journals Myeloid deletion and therapeutic activation of AMP-activated protein kinase (AMPK) do not alter atherosclerosis in male or female mice

2020 ◽  
Author(s):  
Nicholas D. LeBlond ◽  
Peyman Ghorbani ◽  
Conor O’Dwyer ◽  
Nia Ambursley ◽  
Julia R. C. Nunes ◽  
...  
Keyword(s):  
Protein Kinase ◽  
First Generation ◽  
Western Diet ◽  
Daily Injection ◽  
Catalytic Subunits ◽  
Male And Female ◽  
Ampk Signaling ◽  
Female Mice ◽  
Amp Activated Protein Kinase ◽  
Progression Of Atherosclerosis

AbstractObjectiveThe dysregulation of myeloid-derived cell metabolism can drive atherosclerosis. AMP-activated protein kinase (AMPK) controls various aspects of macrophage dynamics and lipid homeostasis, which are important during atherogenesis.Approach and ResultsWe aimed to clarify the role of myeloid-specific AMPK signaling by using LysM-Cre to drive the deletion of both the α1 and α2 catalytic subunits (MacKO), in male and female mice made acutely atherosclerotic by PCSK9-AAV and Western diet-feeding. After 6 weeks of Western diet feeding, half received daily injection of either the AMPK activator, A-769662 or a vehicle control for a further 6 weeks. After 12 weeks, myeloid cell populations were not different between genotype or sex. Similarly, aortic sinus plaque size, lipid staining and necrotic area were not different in male and female MacKO mice compared to their littermate floxed controls. Moreover, therapeutic intervention with A-769662 had no effect. There were no differences in the amount of circulating total cholesterol or triglyceride, and only minor differences in the levels of inflammatory cytokines between groups. Finally, CD68+ area or markers of autophagy showed no effect of either lacking AMPK signaling or systemic AMPK activation.ConclusionsOur data suggest that while defined roles for each catalytic AMPK subunit have been identified, global deletion of myeloid AMPK signaling does not significantly impact atherosclerosis. Moreover, we show that intervention with the first-generation AMPK activator, A-769662, was not able to stem the progression of atherosclerosis.Highlights- The deletion of both catalytic subunits of AMPK in myeloid cells has no significant effect on the progression of atherosclerosis in either male or female mice- Therapeutic delivery of a first-generation AMPK activator (A-769662) for the last 6 weeks of 12-week study had no beneficial effect in either male or female mice- Studying total AMPK deletion may mask specific effects of each isoform and highlights the need for targeted disruption of AMPK phosphorylation sites via knock-in mutations, rather than the traditional “sledgehammer” knockout approach

scholarly journals Cardiovascular function in male and female JCR:LA-cp rats: effect of high-fat/high-sucrose diet

2017 ◽  
Vol 312 (4) ◽  
pp. H742-H751 ◽  
Author(s):  
Ian Hunter ◽  
Amanda Soler ◽  
Gregory Joseph ◽  
Brenda Hutcheson ◽  
Chastity Bradford ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Cardiovascular Function ◽  
Western Diet ◽  
Female Rats ◽  
Male Rats ◽  
High Fat ◽  
Male And Female ◽  
Normal Chow ◽  
High Sucrose

Thirty percent of the world population is diagnosed with metabolic syndrome. High-fat/high-sucrose (HF/HS) diet (Western diet) correlates with metabolic syndrome prevalence. We characterized effects of the HF/HS diet on vascular (arterial stiffness, vasoreactivity, and coronary collateral development) and cardiac (echocardiography) function, oxidative stress, and inflammation in a rat model of metabolic syndrome (JCR rats). Furthermore, we determined whether male versus female animals were affected differentially by the Western diet. Cardiovascular function in JCR male rats was impaired versus normal Sprague-Dawley (SD) rats. HF/HS diet compromised cardiovascular (dys)function in JCR but not SD male rats. In contrast, cardiovascular function was minimally impaired in JCR female rats on normal chow. However, cardiovascular function in JCR female rats on the HF/HS diet deteriorated to levels comparable to JCR male rats on the HF/HS diet. Similarly, oxidative stress was markedly increased in male but not female JCR rats on normal chow but was equally exacerbated by the HF/HS diet in male and female JCR rats. These results indicate that the Western diet enhances oxidative stress and cardiovascular dysfunction in metabolic syndrome and eliminates the protective effect of female sex on cardiovascular function, implying that both males and females with metabolic syndrome are at equal risk for cardiovascular disease. NEW & NOTEWORTHY Western diet abolished protective effect of sex against cardiovascular disease (CVD) development in premenopausal animals with metabolic syndrome. Western diet accelerates progression of CVD in male and female animals with preexisting metabolic syndrome but not normal animals. Exacerbation of baseline oxidative stress correlates with accelerated progression of CVD in metabolic syndrome animals on Western diet.

scholarly journals Knockout of glucose transporter GLUT6 has minimal effects on whole body metabolic physiology in mice

2018 ◽  
Vol 315 (2) ◽  
pp. E286-E293 ◽  
Author(s):  
Frances L. Byrne ◽  
Ellen M. Olzomer ◽  
Robert Brink ◽  
Kyle L. Hoehn
Keyword(s):  
Glucose Transporter ◽  
Gene Expression Pattern ◽  
Western Diet ◽  
Whole Body ◽  
Chow Diet ◽  
Mouse Development ◽  
Wild Type Littermate ◽  
Female Mice ◽  
Transporter Family ◽  
Metabolic Physiology

Glucose transporter 6 (GLUT6) is a member of the facilitative glucose transporter family. GLUT6 is upregulated in several cancers but is not widely expressed in normal tissues. Previous studies have shown that GLUT6 knockdown kills endometrial cancer cells that express elevated levels of the protein. However, whether GLUT6 represents a viable anticancer drug target is unclear because the role of GLUT6 in normal metabolic physiology is unknown. Herein we generated GLUT6 knockout mice to determine how loss of GLUT6 affected whole body glucose homeostasis and metabolic physiology. We found that the mouse GLUT6 ( Slc2a6) gene expression pattern was similar to humans with mRNA found primarily in brain and spleen. CRISPR-Cas9-mediated deletion of Slc2a6 did not alter mouse development, growth, or whole body glucose metabolism in male or female mice fed either a chow diet or Western diet. GLUT6 deletion did not impact glucose tolerance or blood glucose and insulin levels in male or female mice fed either diet. However, compared with wild-type littermate controls, GLUT6 null female mice had a relatively minor decrease in fat accumulation when fed Western diet and had a lower respiratory exchange ratio when fed chow diet. Collectively, these data show that GLUT6 is not a major regulator of whole body metabolic physiology; therefore, GLUT6 inhibition may have minimal adverse effects if targeted for cancer therapy.

scholarly journals Petite Integration Factor 1 (PIF1) helicase deficiency increases weight gain in Western diet-fed female mice without increased inflammatory markers or decreased glucose clearance

2018 ◽  
Author(s):  
Frances R. Belmonte ◽  
Nikolaos Dedousis ◽  
Ian Sipula ◽  
Nikita A. Desai ◽  
Aatur D. Singhi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Weight Gain ◽  
Hepatic Steatosis ◽  
Inflammatory Markers ◽  
Western Diet ◽  
Metabolic Phenotype ◽  
Whole Body ◽  
Chow Diet ◽  
Female Mice ◽  
Glucose Clearance

AbstractPetite Integration Factor 1 (PIF1) is a multifunctional helicase present in nuclei and mitochondria. PIF1 knock out (KO) mice exhibit accelerated weight gain and decreased wheel running on a normal chow diet. In the current study, we investigated whether Pif1 removal alters whole body metabolism in response to weight gain. PIF1 KO and wild type (WT) C57BL/6J mice were fed a Western diet (WD) rich in fat and carbohydrates before evaluation of their metabolic phenotype. Compared with weight gain-resistant WT female mice, WD-fed PIF1 KO females, but not males, showed accelerated adipose deposition, decreased locomotor activity, and reduced whole-body energy expenditure without increased dietary intake. Surprisingly, PIF1 KO females were protected against obesity-induced alterations in fasting blood glucose and glucose clearance. WD-fed PIF1 KO females developed mild hepatic steatosis and associated changes in liver gene expression that were absent in weight-matched, WD-fed female controls, linking hepatic steatosis to Pif1 ablation rather than increased body weight. WD-fed PIF1 KO females also showed decreased gene expression of inflammatory markers in adipose tissue. Collectively, these data separated weight gain from inflammation and impaired glucose homeostasis. They also support a role for Pif1 in weight gain resistance and liver metabolic dysregulation during nutrient stress.

Cystamine reduces vascular stiffness in Western diet-fed female mice

2021 ◽  
Author(s):  
Francisco I. Ramirez-Perez ◽  
Francisco J. Cabral-Amador ◽  
Adam T. Whaley-Connell ◽  
Annayya R Aroor ◽  
Mariana Morales-Quinones ◽  
...  
Keyword(s):  
Tissue Transglutaminase ◽  
Vascular Wall ◽  
Aortic Pulse Wave Velocity ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Mesenteric Arteries ◽  
Chow Diet ◽  
Obese Women ◽  
Arterial Stiffening ◽  
Female Mice

Consumption of diets high in fat, sugar and salt (Western diet, WD) is associated with accelerated arterial stiffening, a major independent risk factor for cardiovascular disease (CVD). Obese women are more prone to develop arterial stiffening leading to more frequent and severe CVD compared to men. As tissue transglutaminase (TG2) has been implicated in vascular stiffening, our goal herein was to determine the efficacy of cystamine, a non-specific TG2 inhibitor, at reducing vascular stiffness in female mice chronically fed a WD. Three experimental groups of female mice were created. One was fed regular chow diet (CD) for 43 weeks starting at four weeks of age. The second was fed a WD for the same 43 weeks, whereas a third cohort was fed WD, but also received cystamine (216 mg/kg/d) in the drinking water during the last eight weeks on the diet (WD+C). All vascular stiffness parameters assessed, including aortic pulse wave velocity and the incremental modulus of elasticity of isolated femoral and mesenteric arteries, were significantly increased in WD- vs. CD-fed mice, and reduced in WD+C vs. WD-fed mice. These changes coincided with respectively augmented and diminished vascular wall collagen and F-actin content, with no associated effect in blood pressure. In cultured human vascular smooth muscle cells, cystamine reduced TG2 activity, F-actin/G-actin ratio, collagen compaction capacity and cellular stiffness. We conclude that cystamine treatment represents an effective approach to reduce vascular stiffness in female mice in the setting of WD consumption, likely due to its TG2 inhibitory capacity.

scholarly journals Endothelial Estrogen Receptor-α Does Not Protect Against Vascular Stiffness Induced by Western Diet in Female Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (4) ◽  
pp. 1590-1600 ◽  
Author(s):  
Camila Manrique ◽  
Guido Lastra ◽  
Francisco I. Ramirez-Perez ◽  
Dominic Haertling ◽  
Vincent G. DeMarco ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Estrogen Receptor ◽  
Vascular Reactivity ◽  
Control Diet ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Whole Body ◽  
Chow Diet ◽  
Female Mice ◽  
Vascular Stiffening

Abstract Consumption of a diet high in fat and refined carbohydrates (Western diet [WD]) is associated with obesity and insulin resistance, both major risk factors for cardiovascular disease (CVD). In women, obesity and insulin resistance abrogate the protection against CVD likely afforded by estrogen signaling through estrogen receptor (ER)α. Indeed, WD in females results in increased vascular stiffness, which is independently associated with CVD. We tested the hypothesis that loss of ERα signaling in the endothelium exacerbates WD-induced vascular stiffening in female mice. We used a novel model of endothelial cell (EC)-specific ERα knockout (EC-ERαKO), obtained after sequential crossing of the ERα double floxed mice and VE-Cadherin Cre-recombinase mice. Ten-week-old females, EC-ERαKO and aged-matched genopairs were fed either a regular chow diet (control diet) or WD for 8 weeks. Vascular stiffness was measured in vivo by pulse wave velocity and ex vivo in aortic explants by atomic force microscopy. In addition, vascular reactivity was assessed in isolated aortic rings. Initial characterization of the model fed a control diet did not reveal changes in whole-body insulin sensitivity, aortic vasoreactivity, or vascular stiffness in the EC-ERαKO mice. Interestingly, ablation of ERα in ECs reduced WD-induced vascular stiffness and improved endothelial-dependent dilation. In the setting of a WD, endothelial ERα signaling contributes to vascular stiffening in females. The precise mechanisms underlying the detrimental effects of endothelial ERα in the setting of a WD remain to be elucidated.

scholarly journals Disruption of CRTC1 and CRTC2 in Sim1 cells strongly increases high-fat diet intake in female mice but has a modest impact on male mice

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262577
Author(s):  
Jin Tanaka ◽  
Fuka Ishikawa ◽  
Tomoki Jinno ◽  
Motoki Miyakita ◽  
Haruka Miyamori ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
High Fat Diet ◽  
Chow Diet ◽  
Male Mice ◽  
High Fat ◽  
Double Knockout ◽  
Female Mice ◽  
Normal Chow ◽  
The Brain ◽  
Regulate Gene

cAMP responsive element binding protein (CREB)-regulated transcription coactivators (CRTCs) regulate gene transcription in response to an increase in intracellular cAMP or Ca2+ levels. To date, three isoforms of CRTC have been identified in mammals. All CRTCs are widely expressed in various regions of the brain. Numerous studies have shown the importance of CREB and CRTC in energy homeostasis. In the brain, the paraventricular nucleus of the hypothalamus (PVH) plays a critical role in energy metabolism, and CRTC1 and CRTC2 are highly expressed in PVH neuronal cells. The single-minded homolog 1 gene (Sim1) is densely expressed in PVH neurons and in some areas of the amygdala neurons. To determine the role of CRTCs in PVH on energy metabolism, we generated mice that lacked CRTC1 and CRTC2 in Sim1 cells using Sim-1 cre mice. We found that Sim1 cell-specific CRTC1 and CRTC2 double-knockout mice were sensitive to high-fat diet (HFD)-induced obesity. Sim1 cell-specific CRTC1 and CRTC2 double knockout mice showed hyperphagia specifically for the HFD, but not for the normal chow diet, increased fat mass, and no change in energy expenditure. Interestingly, these phenotypes were stronger in female mice than in male mice, and a weak phenotype was observed in the normal chow diet. The lack of CRTC1 and CRTC2 in Sim1 cells changed the mRNA levels of some neuropeptides that regulate energy metabolism in female mice fed an HFD. Taken together, our findings suggest that CRTCs in Sim1 cells regulate gene expression and suppress excessive fat intake, especially in female mice.

Sign in / Sign up

Export Citation Format

Share Document