Arcuate nucleus homeostatic systems reflect blood leptin concentration but not feeding behaviour during scheduled feeding on a high-fat diet in mice

Angiotensin (Ang)-(1-7) is a protective hormone of the renin-angiotensin system that improves insulin sensitivity, glucose tolerance, and energy balance in obese rodents. Our recent findings suggest that Ang-(1-7) activates mas receptors (MasR) in the arcuate nucleus of the hypothalamus (ARC), a brain region critical to control of energy balance and glucose homeostasis, to induce these positive metabolic effects. The distribution of MasR in the ARC and their role in metabolic regulation, however, is unknown. We hypothesized: (1) MasR are expressed in the ARC; and (2) deletion of ARC MasR leads to worsened metabolic outcomes following high fat diet (HFD). To test this, male and female C57Bl/6J mice were fed a 60% HFD or matched control diet ad libitum for 12 weeks. RNAscope in situ hybridization was performed on coronal ARC sections in rostral-middle-caudal regions to determine percentage of MasR positive neurons (n=5/group). In a second experiment, we assessed body composition and insulin and glucose tolerance in transgenic mice with deletion of MasR in ARC neurons (MasR-flox with AAV5-hsyn-GFP-Cre). RNAscope revealed a wide distribution on MasR-positive cells throughout the rostral to caudal extent of the ARC. The average percentage of MasR positive neurons was increased in females versus males, with HFD tending to increase MasR expression in both sexes (control diet male: 11±2; control diet female: 17±3; HFD male: 15±5; HFD female: 24±2; p sex : 0.030; p diet : 0.066; p int : 0.615; two-way ANOVA). Deletion of MasR in ARC neurons worsened insulin sensitivity in HFD but not control diet females (area under the curve for change in glucose from baseline: -1989±1359 HFD control virus vs. 2530±1762 HFD Cre virus; p=0.016), while fasting glucose, glucose tolerance, and body composition did not change. There was no effect of ARC MasR deletion on metabolic outcomes in control diet or HFD male mice. These findings suggest females have more MasR positive neurons in the ARC compared to males, which may be a sex-specific protective mechanism for glucose homeostasis. While further studies are needed to explore the role of ARC MasR in metabolic regulation, these findings support targeting Ang-(1-7) as an innovative strategy in obesity.

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The impact of ageing, fasting and high-fat diet on central and peripheral glucose tolerance and glucose-sensing neural networks in the arcuate nucleus

Journal of Neuroendocrinology ◽

10.1111/jne.12528 ◽

2017 ◽

Vol 29 (10) ◽

pp. e12528 ◽

Cited By ~ 4

Author(s):

M. van den Top ◽

F.-Y. Zhao ◽

R. Viriyapong ◽

N. J. Michael ◽

A. C. Munder ◽

...

Keyword(s):

Neural Networks ◽

Glucose Tolerance ◽

High Fat Diet ◽

Arcuate Nucleus ◽

Glucose Sensing ◽

High Fat ◽

The Impact

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Mouse Microglial Calcitonin Receptor Knockout Impairs Hypothalamic Amylin Neuronal pSTAT3 Signaling but Lacks Major Metabolic Consequences

Metabolites ◽

10.3390/metabo12010051 ◽

2022 ◽

Vol 12 (1) ◽

pp. 51

Author(s):

Bernd Coester ◽

Thomas A. Lutz ◽

Christelle Le Foll

Keyword(s):

High Fat Diet ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Calcitonin Receptor ◽

High Fat ◽

Leptin Signaling ◽

Physiological Relevance ◽

Major Player ◽

Significant Difference ◽

Anorectic Effect

Amylin and leptin synergistically interact in the arcuate nucleus of the hypothalamus (ARC) to control energy homeostasis. Our previous rodent studies suggested that amylin-induced interleukin-6 release from hypothalamic microglia may modulate leptin signaling in agouti-related peptide expressing neurons. To confirm the physiological relevance of this finding, the calcitonin receptor (CTR) subunit of the amylin receptor was selectively depleted in microglia by crossing tamoxifen (Tx) inducible Cx3cr1-CreERT2 mice with CTR-floxed mice. Unexpectedly, male mice with CTR-depleted microglia (KO) gained the least amount of weight of all groups regardless of diet. However, after correcting for the tamoxifen effect, there was no significant difference for body weight, fat mass or lean mass between genotypes. No alteration in glucose tolerance or insulin release was detected. However, male KO mice had a reduced respiratory quotient suggesting a preference for fat as a fuel when fed a high fat diet. Importantly, amylin-induced pSTAT3 was decreased in the ARC of KO mice but this was not reflected in a reduced anorectic response. On the other hand, KO mice seemed to be less responsive to leptin’s anorectic effect while displaying similar ARC pSTAT3 as Tx-control mice. Together, these data suggest that microglial amylin signaling is not a major player in the control of energy homeostasis in mice.

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Identification of Sox2 and NeuN Double-Positive Cells in the Mouse Hypothalamic Arcuate Nucleus and Their Reduction in Number With Aging

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.609911 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ayumu Sugiura ◽

Tatsuhiro Shimizu ◽

Takeshi Kameyama ◽

Tomohiko Maruo ◽

Shin Kedashiro ◽

...

Keyword(s):

Stem Cells ◽

High Fat Diet ◽

Arcuate Nucleus ◽

High Fat ◽

Double Positive ◽

Diet Induced Obesity ◽

Hypothalamic Arcuate Nucleus ◽

Hypothalamic Cells ◽

Induced Changes ◽

Insight Into

The hypothalamus plays a central role in homeostasis and aging. The hypothalamic arcuate nucleus (ARC) controls homeostasis of food intake and energy expenditure and retains adult neural stem cells (NSCs)/progenitor cells. Aging induces the loss of NSCs and the enhancement of inflammation, including the activation of glial cells in the ARC, but aging-associated alterations of the hypothalamic cells remain obscure. Here, we identified Sox2 and NeuN double-positive cells in a subpopulation of cells in the mouse ARC. These cells were reduced in number with aging, although NeuN-positive neuronal cells were unaltered in the total number. Diet-induced obesity mice fed with high-fat diet presented a similar hypothalamic alteration to aged mice. This study provides a new insight into aging-induced changes in the hypothalamus.

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Early Overnutrition Results in Early-Onset Arcuate Leptin Resistance and Increased Sensitivity to High-Fat Diet

Endocrinology ◽

10.1210/en.2009-1295 ◽

2010 ◽

Vol 151 (4) ◽

pp. 1598-1610 ◽

Cited By ~ 104

Author(s):

Maria M. Glavas ◽

Melissa A. Kirigiti ◽

Xiao Q. Xiao ◽

Pablo J. Enriori ◽

Sarah K. Fisher ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

High Fat Diet ◽

Arcuate Nucleus ◽

Leptin Resistance ◽

Signal Transducer ◽

High Fat ◽

Insulin Tolerance ◽

Obesity And Diabetes ◽

Transcription 3

Childhood obesity increases the risk of adult obesity and diabetes, suggesting that early overnutrition permanently programs altered energy and glucose homeostasis. In the present studies, we used a mouse model to investigate whether early overnutrition increases susceptibility to obesity and insulin resistance in response to a high-fat diet (HFD). Litters from Swiss Webster dams were culled to three [chronic postnatal overnutrition (CPO)] or 10 (control) pups and then weaned onto standard chow at postnatal day (P) 23. At 6 wk of age, a subset of mice was placed on HFD, and glucose and insulin tolerance were examined at 16–17 wk of age. Leptin sensitivity was determined by hypothalamic phosphorylated signal transducer and activator of transcription-3 immunoreactivity at P16 and adulthood after ip leptin. CPO mice exhibited accelerated body weight gain and hyperleptinemia during the preweaning period but only a slightly heavier body weight and normal glucose tolerance in adulthood on standard chow diet. Importantly, CPO mice exhibited significant leptin resistance in the arcuate nucleus, demonstrated by reduced activation of phospho-signal transducer and activator of transcription-3, as early as P16 and throughout life, despite normalized leptin levels. In response to HFD, CPO but not control mice displayed insulin resistance in response to an insulin tolerance test. In conclusion, CPO mice exhibited early and persistent leptin resistance in the arcuate nucleus and, in response to HFD, rapid development of obesity and insulin resistance. These studies suggest that early overnutrition can permanently alter energy homeostasis and significantly increase susceptibility to obesity and insulin resistance.

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AAV-mediated IL-10 gene transfer counteracts inflammation in the hypothalamic arcuate nucleus and obesity induced by high-fat diet

Neuropeptides ◽

10.1016/j.npep.2016.11.009 ◽

2017 ◽

Vol 62 ◽

pp. 87-92 ◽

Cited By ~ 9

Author(s):

Masanori Nakata ◽

Sawako Yamamoto ◽

Takashi Okada ◽

Toshihiko Yada

Keyword(s):

Gene Transfer ◽

High Fat Diet ◽

Arcuate Nucleus ◽

High Fat ◽

Hypothalamic Arcuate Nucleus

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Food deprivation increases the mRNA expression of μ-opioid receptors in the ventral medial hypothalamus and arcuate nucleus

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00030.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. R1385-R1390 ◽

Cited By ~ 15

Author(s):

Maria J. Barnes ◽

Stefany D. Primeaux ◽

George A. Bray

Keyword(s):

Mrna Expression ◽

Food Deprivation ◽

Opioid Receptors ◽

High Fat Diet ◽

Arcuate Nucleus ◽

High Fat ◽

Low Fat ◽

Low Fat Diet ◽

Medial Hypothalamus ◽

Μ Opioid Receptors

Activation of μ-opioid receptors makes animals hyperphagic and increases their preference for a high-fat diet. Previous studies have suggested that this receptor population plays a role in mediating the hyperphagia that is associated with food deprivation. In this paper, we tested the hypothesis that food deprivation will increase the expression of μ-opioid receptors in the ventral medial hypothalamus and arcuate nucleus (VMH/ARC). Food deprivation resulted in a significant increase in the mRNA expression of μ-opioid receptors in the VMH/ARC and the lateral hypothalamus (LH) after 48 h of fasting but not after 24 or 12 h of fasting in either the light or dark. We did not observe a change in the mRNA expression of κ- or δ-opioid receptors after food deprivation. When food-deprived animals were given a choice between a low-fat diet and a high-fat diet, they were hyperphagic and consumed significantly more of the high-fat diet. When the μ-opioid receptors were blocked with β-funaltrexamine (selective μ-opioid receptor antagonist), prior to giving food-deprived animals access to both a low-fat and high-fat diet, it significantly decreased the percentage of high-fat diet consumed. These data demonstrate that hypothalamic μ-opioid receptors may contribute to the hyperphagia and increased preference for a high-fat diet that is associated with food deprivation.

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High-fat diet feeding reduces the expression of Rab3a, Rab3gap1, and Rab3Gap2 genes that are pivotal to neuronal exocytosis

10.1101/2021.09.10.459820 ◽

2021 ◽

Author(s):

Luana Assis Ferreira ◽

Fernando Victor Martins Rubatino ◽

Mariana Lacerda de Freitas ◽

Leonardo Rossi de Oliveira ◽

Célio Jose de Castro Junior ◽

...

Keyword(s):

Data Analysis ◽

High Fat Diet ◽

Arcuate Nucleus ◽

Control Diet ◽

Receptor Recycling ◽

High Fat ◽

Transcript Levels ◽

General Network ◽

Obesity Phenotype ◽

Plasma Leptin

AbstractThe Rab3A and Rab3gaps are essential to the Ca+2-dependent neuronal exocytosis in the hypothalamus. The arcuate nucleus of the hypothalamus (ARC) controls food intake and energy expenditure. We have earlier described that the high-fat diet (HFD) feeding induces an obesity phenotype with high leptin production and alteration of proteins related to endosome sorting, and ubiquitination in the ARC of mice. In this study, real-time PCR data analysis revealed that HFD feeding decreases significantly Rab3a, Rab3gap1, and Rab3gap2 transcript levels in the ARC when compared to the group receiving a control diet. The decrease of Rab3gap1/2 transcript levels in the ARC was strongly associated with an increase in plasma leptin. Altogether, our studies demonstrate that HFD feeding could be altering the general network of endosome compartmentalization in the ARC of mice, contributing to a failure in exocytosis and receptor recycling.Graphical abstract

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