Tamoxifen treatment in the neonatal period affects glucose homeostasis in adult mice in a sex-dependent manner

Endocrinology ◽  
2021 ◽  
Author(s):  
Judith Estrada-Meza ◽  
Jasmine Videlo ◽  
Clara Bron ◽  
Cécile Saint-Béat ◽  
Marine Silva ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Tamoxifen Treatment ◽  
Dependent Manner ◽  
Bone Biology ◽  
Male And Female ◽  
Adult Mice ◽  
Receptor Modulator ◽  
Insulin Tolerance ◽  
Somatic Mutagenesis

Abstract Tamoxifen is a selective estrogen receptor modulator used to activate the CRE ERT2 recombinase, allowing tissue-specific and temporal control of the somatic mutagenesis to generate transgenic mice. Studies integrating development and metabolism require a genetic modification induced by a neonatal tamoxifen administration. Here, we investigate the effects of a neonatal tamoxifen administration on energy homeostasis in adult male and female C57BL/6J mice. C57BL/6J male and female mouse pups received a single injection of tamoxifen one day after birth (NTT) and were fed a high-fat/high-sucrose (HF/HS) diet at 6 weeks of age. We measured weight, body composition, glucose and insulin tolerance, basal metabolism and tibia length and weight in adult mice. The neonatal tamoxifen administration exerted long-term, sex-dependent effects on energy homeostasis. NTT female mice became overweight and developed impaired glucose control in comparison to vehicle-treated littermates. NTT females exhibited 60% increased fat mass, increased food intake, decreased physical activity and decreased energy expenditure, impaired glucose and insulin tolerance, and fasting hyperglycemia and hyperinsulinemia. In contrast, NTT male mice exhibited a modest amelioration of glucose and insulin tolerance, and long-term decreased lean mass linked to decreased bone weight. These results suggest that the neonatal tamoxifen administration exerted a marked and sex-dependent influence on adult energy homeostasis and bone weight, and must therefore be used with caution for the development of transgenic mouse models regarding studies on energy homeostasis and bone biology.

scholarly journals Hypothalamic γ-melanocyte stimulating hormone gene delivery reduces fat mass in male mice

2018 ◽  
Vol 239 (1) ◽  
pp. 19-31 ◽  
Author(s):  
K Eerola ◽  
S Virtanen ◽  
L Vähätalo ◽  
L Ailanen ◽  
M Cai ◽  
...  
Keyword(s):  
Weight Loss ◽  
Energy Balance ◽  
Gene Delivery ◽  
Fat Mass ◽  
Energy Homeostasis ◽  
Western Diet ◽  
Dependent Manner ◽  
Melanocyte Stimulating Hormone ◽  
Stimulating Hormone

γ-Melanocyte stimulating hormone (γ-MSH) is an endogenous agonist of the melanocortin 3-receptor (MC3R). Genetic disruption of MC3Rs increases adiposity and blunts responses to fasting, suggesting that increased MC3R signaling could be physiologically beneficial in the long term. Interestingly, several studies have concluded that activation of MC3Rs is orexigenic in the short term. Therefore, we aimed to examine the short- and long-term effects of γ-MSH in the hypothalamic arcuate nucleus (ARC) on energy homeostasis and hypothesized that the effect of MC3R agonism is dependent on the state of energy balance and nutrition. Lentiviral gene delivery was used to induce a continuous expression of γ-Msh only in the ARC of male C57Bl/6N mice. Parameters of body energy homeostasis were monitored as food was changed from chow (6 weeks) to Western diet (13 weeks) and back to chow (7 weeks). The γ-MSH treatment decreased the fat mass to lean mass ratio on chow, but the effect was attenuated on Western diet. After the switch back to chow, an enhanced loss in weight (−15% vs −6%) and fat mass (−37% vs −12%) and reduced cumulative food intake were observed in γ-MSH-treated animals. Fasting-induced feeding was increased on chow diet only; however, voluntary running wheel activity on Western diet was increased. The γ-MSH treatment also modulated the expression of key neuropeptides in the ARC favoring weight loss. We have shown that a chronic treatment intended to target ARC MC3Rs modulates energy balance in nutritional state-dependent manner. Enhancement of diet-induced weight loss could be beneficial in treatment of obesity.

Central Administration of the Ciliary Neurotrophic Factor Analogue, Axokine, Does Not Play a Role in Long-Term Energy Homeostasis in Adult Mice

2015 ◽  
Vol 103 (3-4) ◽  
pp. 223-229 ◽  
Author(s):  
Melissa L. Borg ◽  
Alex Reichenbach ◽  
Moyra Lemus ◽  
Brian J. Oldfield ◽  
Zane B. Andrews ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Energy Homeostasis ◽  
Ciliary Neurotrophic Factor ◽  
Central Administration ◽  
Adult Mice ◽  
Term Energy

scholarly journals Litter expansion alters metabolic homeostasis in a sexually divergent manner

2020 ◽  
Author(s):  
Kavitha Kurup ◽  
Shivani N Mann ◽  
Jordan Jackson ◽  
Stephanie Matyi ◽  
Michelle Ranjo-Bishop ◽  
...  
Keyword(s):  
Brain Cortex ◽  
Male Mice ◽  
Long Term Effects ◽  
Male And Female ◽  
Insulin Tolerance ◽  
Total Fat ◽  
Fat Depot ◽  
The Brain ◽  
Robust Response

AbstractNutritional manipulations early in life have been shown to influence growth rate and elicit long lasting effects which in turn has been found to impact lifespan. Therefore, we studied the long-term effects of pre-weaning dietary restriction implemented by litter expansion (4, 6, 8, 10, and 12 pups per dam: LS4, LS6, LS8, LS10, LS12) on male and female C57BL/6 mice. After weaning, these mice were fed ad libitum a commercial lab chow for the 15-month duration of the study. The mice from large litter sizes (LS12) were significantly leaner and had reduced total fat mass compared to the normal size litters (LS 6) starting from weaning through to 15 months of age. Male LS10 & 12 mice showed significant reduction in their fat depot masses at 15 months of age: gonadal, subcutaneous, and brown fat whereas the females did not mimic these findings. At 9 months of age, both male and female LS10 and 12 mice showed improved glucose tolerance; however, only male LS10 and LS12 mice showed improved insulin tolerance starting at 5 months of age. In addition, we found that the male LS8, 10 & 12 mice at 15 months of age showed significantly reduced IGF-1 levels in the serum and various other organs (liver, gastrocnemius and brain cortex). Interestingly, the female LS8, 10, 12 mice showed a different pattern with reduced IGF-1 levels in serum, liver and gastrocnemius but not in the brain cortex. Similarly, the litter expanded mice showed sexual divergence in levels of FGF21 and adiponectin with only the male mice showing increased FGF21 and adiponectin levels at 15 months of age. In summary, our data show that, litter expansion results in long-lasting metabolic changes that are age and sex dependent with the male mice showing an early and robust response compared to female mice.

scholarly journals Gpr17 deficiency in POMC neurons ameliorates the metabolic derangements caused by long-term high-fat diet feeding

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Austin M. Reilly ◽  
Shudi Zhou ◽  
Sunil K. Panigrahi ◽  
Shijun Yan ◽  
Jason M. Conley ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Energy Homeostasis ◽  
Regulatory Function ◽  
Chow Diet ◽  
Dependent Manner ◽  
Metabolic Homeostasis ◽  
High Fat ◽  
Electrophysiological Properties ◽  
Insulin Tolerance ◽  
Normal Chow

Abstract Background Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) control energy homeostasis by sensing hormonal and nutrient cues and activating secondary melanocortin sensing neurons. We identified the expression of a G protein-coupled receptor, Gpr17, in the ARH and hypothesized that it contributes to the regulatory function of POMC neurons on metabolism. Methods In order to test this hypothesis, we generated POMC neuron-specific Gpr17 knockout (PGKO) mice and determined their energy and glucose metabolic phenotypes on normal chow diet (NCD) and high-fat diet (HFD). Results Adult PGKO mice on NCD displayed comparable body composition and metabolic features measured by indirect calorimetry. By contrast, PGKO mice on HFD demonstrated a sexually dimorphic phenotype with female PGKO mice displaying better metabolic homeostasis. Notably, female PGKO mice gained significantly less body weight and adiposity (p < 0.01), which was associated with increased energy expenditure, locomotor activity, and respiratory quotient, while males did not have an overt change in energy homeostasis. Though PGKO mice of both sexes had comparable glucose and insulin tolerance, detailed analyses of liver gene expression and serum metabolites indicate that PGKO mice could have reduced gluconeogenesis and increased lipid utilization on HFD. To elucidate the central-based mechanism(s) underlying the better-preserved energy and glucose homeostasis in PGKO mice on HFD, we examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, PGKO mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. Conclusions Gpr17 deficiency in POMC neurons protects metabolic homeostasis in a sex-dependent manner during dietary and aging challenges, suggesting that Gpr17 could be an effective anti-obesity target in specific populations with poor metabolic control.

scholarly journals Activation of the central melanocortin system chronically reduces body mass without the necessity of long-term caloric restriction

2017 ◽  
Vol 95 (2) ◽  
pp. 206-214 ◽  
Author(s):  
I. Côté ◽  
Y. Sakarya ◽  
N. Kirichenko ◽  
D. Morgan ◽  
C.S. Carter ◽  
...  
Keyword(s):  
Energy Balance ◽  
Caloric Restriction ◽  
Body Mass ◽  
Energy Homeostasis ◽  
Control Level ◽  
Negative Energy ◽  
Dependent Manner ◽  
Melanocortin System ◽  
Balance State

Melanotan II (MTII) is a potent appetite suppressor that rapidly reduces body mass. Given the rapid loss of anorexic response upon chronic MTII treatment, most investigations have focused on the initial physiological adaptations. However, other evidence supports MTII as a long-term modulator of energy balance that remains to be established. Therefore, we examined the chronic effects of MTII on energy homeostasis. MTII (high or low dose) or artificial cerebrospinal fluid (aCSF) was infused into the lateral ventricle of the brain of 6-month-old F344BN rats (6–7/group) over 40 days. MTII suppressed appetite in a dose-dependent manner (P < 0.05). Although food intake promptly rose back to control level, body mass was persistently reduced in both MTII groups (P < 0.01). At day 40, both MTII groups displayed lower adiposity than the aCSF animals (P < 0.01). These results show that MTII chronically reduces body mass without the requirement of long-term caloric restriction. Our study proposes that food restriction helps initiate mass loss; however, combined with a secondary pharmacological approach preserving a negative energy balance state over time may help combat obesity.

scholarly journals The Long-Term Impact of High Levels of Alpha-Melanocyte-Stimulating Hormone in Energy Balance Among Obese Adolescents

2018 ◽  
Vol 72 (4) ◽  
pp. 279-286 ◽  
Author(s):  
Ana Claudia Pelissari Kravchychyn ◽  
Raquel Munhoz da Silveira Campos ◽  
Flávia Campos Corgosinho ◽  
Deborah Cristina Landi Masquio ◽  
Sofia Emanuelle de Castro Ferreira Vicente ◽  
...  
Keyword(s):  
Weight Loss ◽  
Energy Balance ◽  
Energy Homeostasis ◽  
Fat Free Mass ◽  
Dependent Manner ◽  
Obese Adolescents ◽  
Melanocyte Stimulating Hormone ◽  
Weight Loss Therapy ◽  
Stimulating Hormone

Background: Deregulation of orexigenic and anorexigenic pathways occurs among adolescents with obesity. Alpha-melanocyte-stimulating hormone (α-MSH) is a key catabolic mediator of energy homeostasis and an important anorexigenic neuropeptide in the control of energy balance and thermogenesis. However, it was not well explored if α-MSH can modulate long-term weight loss therapy responses in a dependent manner according to its concentration. Our hypothesis is that a high α-MSH concentration at baseline promotes better modulation of anorexigenic/orexigenic pathways in obese adolescents. Methods: One hundred ten post-pubertal obese adolescents (body mass index >95th percentile) were submitted to 1 year of interdisciplinary therapy (clinical, nutritional, psychological, physical exercise, and physiotherapy support). Body composition and plasma levels of α-MSH, neuropeptide Y (NPY), melanin-concentrating hormone, and agouti-related peptide (AgRP) were measured before and after therapy. The volunteers were grouped on the basis of Tertiles of α-MSH concentration: Low (<0.75 ng/mL), Medium (≤0.76 to ≥1.57 ng/mL), and High (>1.57 ng/mL). Significance was set as p < 0.05. Results: The treatment promoted a significant improvement in body adiposity and fat free mass for all groups. It is important to note that only in the high α-MSH group, a significant increase of the α-MSH/NPY ratio and decrease NPY/AgRP ratio post treatment were observed. Conclusion: The high α-MSH concentration promotes better modulation of anorexigenic/orexigenic pathways in obese adolescents following long-term weight loss therapy and this is important in clinical practice.

scholarly journals OR16-03 Metabolic Effects Of Hypothalamic Pomc Neurons Generated Postnatally From Tanycytes On A Pomc Null Genetic Background

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Surbhi Gahlot ◽  
Gabor Wittmann ◽  
Ronald M Lechan ◽  
Malcolm J Low
Keyword(s):  
Adult Stem Cells ◽  
Energy Homeostasis ◽  
Third Ventricle ◽  
Metabolic Effects ◽  
Tamoxifen Treatment ◽  
Melanocortin System ◽  
Genetic Mouse Model ◽  
Adult Mice ◽  
Novel Approach ◽  
Obesity Phenotype

Abstract Hypothalamic proopiomelanocortin (POMC) neurons are an integral part of the central melanocortin system and regulate feeding and energy balance in vertebrates. Tanycytes are radial glial-like cells lining the third ventricle that contain a subpopulation of adult stem cells, which can differentiate under specific circumstances into glia and neurons, including POMC neurons. However, the capacity of these stem cell-derived neurons to fully mature and integrate into existing neural circuits of physiological relevance is unknown. This study systematically tested whether Pomc mRNA-positive cells newly generated from tanycyte precursors can differentiate into melanocortin-secreting POMC neurons, integrate into the normal anatomical projection pathways of these cells and rescue the obesity phenotype caused by the loss of Pomc expression in ArcPomcfneo/fneo mice. We generated an inducible compound genetic mouse model by crossing RaxCreERT2 with the Cre-dependent ArcPomcfneo/fneo and LSL-syp-tdTomato alleles. Rax is expressed exclusively in postnatal tanycytes, thereby limiting tamoxifen-induced recombination of the two floxed alleles by CreERT2 to tanycytes. As expected, tamoxifen treatment of the mice at age 4–5 wk recapitulated endogenous Rax expression 16 wk later as observed by red fluorescent tdTomato expression in all tanycytes. In addition, Cre recombinase-mediated deletion of the floxed-neomycin cassette from the neuronal enhancer region of the ArcPomcfneo alleles relieved their constitutive transcriptional silencing. Consequently, tamoxifen treatment consistently generated a significant number of newly generated POMC neurons from tanycytes (~10% of the POMC neurons in a WT mouse), identified by Pomc FISH and POMC/α-MSH immunofluorescence in the soma and established terminal projections to hypothalamic nuclei including the PVH and DMH involved in energy homeostasis. A subpopulation of these neurons also expressed the synaptophysin-tDTomato reporter. We performed serial body weight, food intake, body composition, oral GTT and insulin measurements with the RaxCreERT2/+, ArcPomcfneo/fneo mice and found no significant differences in any of these metabolic variables compared to untreated obese ArcPomcfneo/fneo mice. These data are consistent with previous studies from our lab suggesting that Pomc expression has to be at least ~30% of normal to mitigate the obesity phenotype in Pomc-null mice. In conclusion, we demonstrated that tanycytes are capable of generating mature Pomc-expressing neurons in the hypothalamus of adult mice. However, we propose that determining the underlying mechanisms involved in the generation of hypothalamic POMC neurons from tanycytes and interventions to increase their number, might lead to a novel approach to treat obesity. Nothing to Disclose: SG, GW, RML, MJL

scholarly journals NMDA Receptor-Dependent Synaptic Depression in Potentiated Synapses of the Anterior Cingulate Cortex of adult Mice

2021 ◽  
Vol 17 ◽  
pp. 174480692110180
Author(s):  
Man Xue ◽  
Si-Bo Zhou ◽  
Ren-Hao Liu ◽  
Qi-Yu Chen ◽  
Min Zhuo ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Nmda Receptor ◽  
Anterior Cingulate Cortex ◽  
Cingulate Cortex ◽  
Synaptic Depression ◽  
Anterior Cingulate ◽  
Dependent Manner ◽  
Selective Antagonist ◽  
Adult Mice

Long-term potentiation (LTP) is an important molecular mechanism for chronic pain in the anterior cingulate cortex (ACC), a key cortical region for pain perception and emotional regulation. Inhibiting ACC LTP via various manipulations or pharmacological treatments blocks chronic pain. Long-term depression (LTD) is another form of synaptic plasticity in the ACC, which is also proved to be involved in the mechanisms of chronic pain. However, less is known about the interactive relationship between LTP and LTD in the ACC. Whether the synaptic depression could be induced after synaptic LTP in the ACC is not clear. In the present study, we used multi-channel field potential recording systems to study synaptic depression after LTP in the ACC of adult mice. We found that low frequency stimulus (LFS: 1 Hz, 15 min) inhibited theta burst stimulation (TBS)-induced LTP at 30 min after the induction of LTP. However, LFS failed to induce depression at 90 min after the induction of LTP. Furthermore, NMDA receptor antagonist AP-5 blocked the induction of synaptic depression after potentiation. The GluN2B-selective antagonist Ro25-6981 also inhibited the phenomenon in the ACC, while the GluN2A-selective antagonist NVP-AAM077 and the GluN2C/D-selective antagonist PPDA and UBP145 had no any significant effect. These results suggest that synaptic LTP can be depressed by LTD in a time dependent manner, and GluN2B-containing NMDA receptors play important roles in this form of synaptic depression.

scholarly journals Deletion of the Rab GAP Tbc1d1 modifies glucose, lipid, and energy homeostasis in mice

2015 ◽  
Vol 309 (3) ◽  
pp. E233-E245 ◽  
Author(s):  
Stefan R. Hargett ◽  
Natalie N. Walker ◽  
Syed S. Hussain ◽  
Kyle L. Hoehn ◽  
Susanna R. Keller
Keyword(s):  
Skeletal Muscle ◽  
Cell Surface ◽  
Glucose Uptake ◽  
Skeletal Muscles ◽  
Energy Homeostasis ◽  
Glucose Transporter ◽  
Whole Body ◽  
Acid Oxidation ◽  
Dependent Manner ◽  
Male And Female

Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1−/−) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1−/− mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1−/− mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1−/− mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1−/− mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1−/− mice and between male Tbc1d1−/− mice in different studies due to variations in body composition and nutrient handling.

The Neurobiology of Pain

2019 ◽  
pp. 387-414
Author(s):  
Maria Fitzgerald ◽  
Michael W. Salter
Keyword(s):  
Early Life ◽  
Pain Perception ◽  
Long Term Effects ◽  
Male And Female ◽  
Functional Changes ◽  
Pain Pathways ◽  
Developmental Age ◽  
Short And Long Term ◽  
Age And Sex

The influence of development and sex on pain perception has long been recognized but only recently has it become clear that this is due to specific differences in underlying pain neurobiology. This chapter summarizes the evidence for mechanistic differences in male and female pain biology and for functional changes in pain pathways through infancy, adolescence, and adulthood. It describes how both developmental age and sex determine peripheral nociception, spinal and brainstem processing, brain networks, and neuroimmune pathways in pain. Finally, the chapter discusses emerging evidence for interactions between sex and development and the importance of sex in the short- and long-term effects of early life pain.

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