scholarly journals Treatment with Soluble Activin Type IIB Receptor Ameliorates Ovariectomy-Induced Bone Loss and Fat Gain in Mice

2022 ◽  
Author(s):  
Tero Puolakkainen ◽  
Petri Rummukainen ◽  
Vappu Pihala-Nieminen ◽  
Olli Ritvos ◽  
Eriika Savontaus ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Bone Mass ◽  
Postmenopausal Osteoporosis ◽  
Metabolic Effects ◽  
Hormonal Changes ◽  
Micro Computed Tomography ◽  
Metabolic Alterations ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
And Function

Abstract Introduction In postmenopausal osteoporosis, hormonal changes lead to increased bone turnover and metabolic alterations including increased fat mass and insulin resistance. Activin type IIB receptors bind several growth factors of the TGF-β superfamily and have been demonstrated to increase muscle and bone mass. We hypothesized that ActRIIB-Fc treatment could improve bone and muscle mass, inhibit fat accumulation, and restore metabolic alterations in an ovariectomy (OVX) model of postmenopausal osteoporosis. Materials and Methods Female C57Bl/6 N mice were subjected to SHAM or OVX procedures and received intraperitoneal injections of either PBS or ActRIIB-Fc (5 mg/kg) once weekly for 7 weeks. Glucose and insulin tolerance tests (GTT and ITT, respectively) were performed at 7 and 8 weeks, respectively. Bone samples were analyzed with micro-computed tomography imaging, histomorphometry, and quantitative RT-PCR. Results Bone mass decreased in OVX PBS mice compared to the SHAM PBS group but ActRIIB-Fc was able to prevent these changes as shown by µCT and histological analyses. This was due to decreased osteoclast numbers and function demonstrated by histomorphometric and qRT-PCR analyses. OVX induced adipocyte hypertrophy that was rescued by ActRIIB-Fc, which also decreased systemic adipose tissue accumulation. OVX itself did not affect glucose levels in GTT but ActRIIB-Fc treatment resulted in impaired glucose clearance in both SHAM and OVX groups. OVX induced mild insulin resistance in ITT but ActRIIB-Fc treatment did not affect this. Conclusion Our results reinforce the potency of ActRIIB-Fc as a bone-enhancing agent but also bring new insight into the metabolic effects of ActRIIB-Fc in normal and OVX mice.

Effect of a Polyphenol-Rich Extract from Aloe vera Gel on Experimentally Induced Insulin Resistance in Mice

2007 ◽  
Vol 35 (06) ◽  
pp. 1037-1046 ◽  
Author(s):  
Yolanda Y. Pérez ◽  
Enrique Jiménez-Ferrer ◽  
Alejandro Zamilpa ◽  
Marcelino Hernández-Valencia ◽  
Francisco J. Alarcón-Aguilar ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Aloe Vera ◽  
Negative Control Group ◽  
Negative Control ◽  
Control Group ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
Aloe Vera Gel ◽  
Experimentally Induced

Insulin resistance, which precedes type 2 diabetes mellitus (T2DM), is a widespread pathology associated with the metabolic syndrome, myocardial ischemia, and hypertension. Finding an adequate treatment for this pathology is an important goal in medicine. The purpose of the present research was to investigate the effect of an extract from Aloe vera gel containing a high concentration of polyphenols on experimentally induced insulin resistance in mice. A polyphenol-rich Aloe vera extract (350 mg/kg) with known concentrations of aloin (181.7 mg/g) and aloe-emodin (3.6 mg/g) was administered orally for a period of 4 weeks to insulin resistant ICR mice. Pioglitazone (50 mg/kg) and bi-distilled water were used as positive and negative controls respectively. Body weight, food intake, and plasma concentrations of insulin and glucose were measured and insulin tolerance tests were performed. The insulin resistance value was calculated using the homeostasis model assessment for insulin resistance (HOMA-IR) formula. Results showed that the polyphenol-rich extract from Aloe vera was able to decrease significantly both body weight ( p < 0.008) and blood glucose levels ( p < 0.005) and to protect animals against unfavorable results on HOMA-IR, which was observed in the negative control group. The highest glucose levels during the insulin tolerance curve test were in the negative control group when compared to the Aloe vera extract and pioglitazone treated mice ( p < 0.05). In conclusion, Aloe vera gel could be effective for the control of insulin resistance.

scholarly journals CYP2J2 attenuates metabolic dysfunction in diabetic mice by reducing hepatic inflammation via the PPARγ

2015 ◽  
Vol 308 (4) ◽  
pp. E270-E282 ◽  
Author(s):  
Rui Li ◽  
Xizhen Xu ◽  
Chen Chen ◽  
Yan Wang ◽  
Artiom Gruzdev ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Biological Effects ◽  
Tolerance Test ◽  
Mapk Signaling ◽  
Metabolic Dysfunction ◽  
Glucose Levels ◽  
Hepatic Cells ◽  
Insulin Tolerance

Epoxyeicosatrienoic acids (EETs) and arachidonic acid-derived cytochrome P450 (CYP) epoxygenase metabolites have diverse biological effects, including anti-inflammatory properties in the vasculature. Increasing evidence suggests that inflammation in type 2 diabetes is a key component in the development of insulin resistance. In this study, we investigated whether CYP epoxygenase expression and exogenous EETs can attenuate insulin resistance in diabetic db/db mice and in cultured hepatic cells (HepG2). In vivo, CYP2J2 expression and the accompanying increase in EETs attenuated insulin resistance, as determined by plasma glucose levels, glucose tolerance test, insulin tolerance test, and hyperinsulinemic euglycemic clamp studies. CYP2J2 expression reduced the production of proinflammatory cytokines in liver, including CRP, IL-6, IL-1β, and TNFα, and decreased the infiltration of macrophages in liver. CYP2J2 expression also decreased activation of proinflammatory signaling cascades by decreasing NF-κB and MAPK activation in hepatocytes. Interestingly, CYP2J2 expression and exogenous EET treatment increased glucose uptake and activated the insulin-signaling cascade both in vivo and in vitro, suggesting that CYP2J2 metabolites play a role in glucose homeostasis. Furthermore, CYP2J2 expression upregulated PPARγ, which has been shown to induce adipogenesis, which attenuates dyslipidemias observed in diabetes. All of the findings suggest that CYP2J2 expression attenuates the diabetic phenotype and insulin resistance via inhibition of NF-κB and MAPK signaling pathways and activation of PPARγ.

scholarly journals Beneficial Metabolic Effects of TREM2 in Obesity are Uncoupled from its Expression on Macrophages

2021 ◽  
Author(s):  
Omar Sharif ◽  
Julia Stefanie Brunner ◽  
Ana Korosec ◽  
Rui Martins ◽  
Alexander Jais ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Immune Cell ◽  
Metabolic Effects ◽  
Sphingolipid Metabolism ◽  
Protective Effects ◽  
Tissue Macrophage ◽  
Insulin Tolerance ◽  
Ceramide Synthesis

Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated ATM-expressed TREM2 promoted health. Here, we identified that in mice TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell-expressed TREM2 on health instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in TREM2’s systemic protective effects on metabolic health.

scholarly journals Suppression of Prolactin Secretion Partially Explains the Antidiabetic Effect of Bromocriptine in ob/ob Mice

Endocrinology ◽  
2018 ◽  
Vol 160 (1) ◽  
pp. 193-204 ◽  
Author(s):  
Isadora C Furigo ◽  
Miriam F Suzuki ◽  
João E Oliveira ◽  
Angela M Ramos-Lobo ◽  
Pryscila D S Teixeira ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Prolactin Secretion ◽  
Dopamine Receptor Agonist ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Insulin Tolerance ◽  
Promising Therapeutic Approach

Abstract Previous studies have shown that bromocriptine mesylate (Bromo) lowers blood glucose levels in adults with type 2 diabetes mellitus; however, the mechanism of action of the antidiabetic effects of Bromo is unclear. As a dopamine receptor agonist, Bromo can alter brain dopamine activity affecting glucose control, but it also suppresses prolactin (Prl) secretion, and Prl levels modulate glucose homeostasis. Thus, the objective of the current study was to investigate whether Bromo improves insulin sensitivity via inhibition of Prl secretion. Male and female ob/ob animals (a mouse model of obesity and insulin resistance) were treated with Bromo and/or Prl. Bromo-treated ob/ob mice exhibited lower serum Prl concentration, improved glucose and insulin tolerance, and increased insulin sensitivity in the liver and skeletal muscle compared with vehicle-treated mice. Prl replacement in Bromo-treated mice normalized serum Prl concentration without inducing hyperprolactinemia. Importantly, Prl replacement partially reversed the improvements in glucose homeostasis caused by Bromo treatment. The effects of the Prl receptor antagonist G129R-hPrl on glucose homeostasis were also investigated. We found that central G129R-hPrl infusion increased insulin tolerance of male ob/ob mice. In summary, our findings indicate that part of Bromo effects on glucose homeostasis are associated with decrease in serum Prl levels. Because G129R-hPrl treatment also improved the insulin sensitivity of ob/ob mice, pharmacological compounds that inhibit Prl signaling may represent a promising therapeutic approach to control blood glucose levels in individuals with insulin resistance.

scholarly journals Changes in insulin resistance do not occur in parallel with changes in mitochondrial content and function in male rats

2020 ◽  
Author(s):  
Amanda J Genders ◽  
Jujiao Kuang ◽  
Evelyn C Marin ◽  
Nicholas J Saner ◽  
Javier Botella ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Exercise Training ◽  
Mitochondrial Respiration ◽  
High Fat Diet ◽  
Respiratory Function ◽  
High Fat ◽  
Mitochondrial Content ◽  
Insulin Tolerance ◽  
And Function ◽  
Mitochondrial Respiratory

AbstractAims/hypothesisTo investigate if there is a causal relationship between changes in insulin resistance and mitochondrial respiratory function and content in rats fed a high fat diet (HFD) with or without concurrent exercise training. We hypothesised that provision of a high fat diet (HFD) would increase insulin resistance and decrease mitochondrial characteristics (content and function), and that exercise training would improve both mitochondrial characteristics and insulin resistance in rats fed a HFD.MethodsMale Wistar rats were given either a chow diet or a high fat diet (HFD) for 12 weeks. After 4 weeks of the dietary intervention, half of the rats in each group began eight weeks of interval training. In vivo glucose and insulin tolerance was assessed, as was ex vivo glucose uptake in epitrochlearis muscle. Mitochondrial respiratory function was assessed in permeabilised soleus and white gastrocnemius (WG) muscles. Mitochondrial content was determined by measurement of citrate synthase (CS) activity and protein expression of components of the electron transport system (ETS).ResultsHFD rats had impaired glucose and insulin tolerance. HFD did not change CS activity in the soleus; however, it did increase CS activity in WG (Chow 5.9 ± 0.5, HFD 7.2 ± 0.7 mol h-1 kg protein-1). Protein expression of components of the ETS and mitochondrial respiratory function (WG Chow 65.2 ± 8.4, HFD 88.6 ± 8.7 pmol O2 s-1 mg-1) were also increased by HFD. Exercise training improved glucose and insulin tolerance in the HFD rats. Exercise training did not alter CS activity in either muscle. Mitochondrial respiratory function was increased with exercise training in the chow fed animals in soleus muscle, but not in WG. This exercise effect was absent in the HFD animals. Mitochondrial characteristics did not consistently correlate with insulin or glucose tolerance.Conclusions/interpretationHFD induced insulin resistance, but it did not negatively affect any of the measured mitochondrial characteristics. Exercise training improved insulin resistance, but without changes in mitochondrial respiration and content. The lack of an association between mitochondrial characteristics and insulin resistance was reinforced by the absence of strong correlations between these measures. Our results suggest that defects in mitochondrial respiration and content are not responsible for insulin resistance in HFD rats.

scholarly journals Acute psychological stress results in the rapid development of insulin resistance

2013 ◽  
Vol 217 (2) ◽  
pp. 175-184 ◽  
Author(s):  
Li Li ◽  
Xiaohua Li ◽  
Wenjun Zhou ◽  
Joseph L Messina
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Insulin Receptor ◽  
Psychological Stress ◽  
Insulin Signaling ◽  
Rapid Development ◽  
Whole Body ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
Acute Psychological Stress

In recent years, the roles of chronic stress and depression as independent risk factors for decreased insulin sensitivity and the development of diabetes have been increasingly recognized. However, an understanding of the mechanisms linking insulin resistance and acute psychological stress are very limited. We hypothesized that acute psychological stress may cause the development of insulin resistance, which may be a risk factor in developing type 2 diabetes. We tested the hypothesis in a well-established mouse model using 180 episodes of inescapable foot shock (IES) followed by a behavioral escape test. In this study, mice that received IES treatment were tested for acute insulin resistance by measuring glucose metabolism and insulin signaling. When compared with normal and sham mice, mice that were exposed to IES resulting in escape failure (defined as IES with behavioral escape failure) displayed elevated blood glucose levels in both glucose tolerance and insulin tolerance tests. Furthermore, mice with IES exposure and behavioral escape failure exhibited impaired hepatic insulin signaling via the insulin-induced insulin receptor/insulin receptor substrate 1/Akt pathway, without affecting similar pathways in skeletal muscle, adipose tissue, and brain. Additionally, a rise in the murine growth-related oncogene KC/GRO was associated with impaired glucose metabolism in IES mice, suggesting a mechanism by which psychological stress by IES may influence glucose metabolism. The present results indicate that psychological stress induced by IES can acutely alter hepatic responsiveness to insulin and affect whole-body glucose metabolism.

Metabolic effects of calcitonin in the newborn

1975 ◽  
Vol 229 (3) ◽  
pp. 669-675 ◽  
Author(s):  
JM Garel ◽  
JP Barlet ◽  
A Kervran
Keyword(s):  
Amino Acids ◽  
Plasma Lipids ◽  
Insulin Level ◽  
Metabolic Effects ◽  
Hormonal Changes ◽  
Newborn Rats ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Amino Acid Levels ◽  
Physiological Dose

Calcitonin was injected in newborn rats and newborn lambs to study the metabolic effects of the hormone. Subcutaneous injection of salmon calcitonin (140 MRC U/kg) induced a clearing effect on plasma from suckling newborn rats that was naturally lactescent. A lower dose given by the same route (14 MRC U/kg) strongly decreased plasma triglyceride and amino acid levels in suckling newborn rats. This was mainly the result of gastric emptying inhibition. The gastrointestinal action of calcitonin in suckling newborn rats was substantiated by the absorption of [14C]triolein and 14C-labeled amino acids. Hormonal changes that were associated were a decrease in plasma insulin level and an increase in plasma growth hormone concentration. Intravenous calcitonin at a physiological dose (0.03 MRC U/kg) injected into newborn lambs inhibited increases in total plasma lipids, amino acids, and blood-glucose levels at the time of the first suckling period without changing serum calcium levels. One of the physiological roles of calcitonin in the newborn may be the regulation of nutrient absorption from milk rich in lipids.

scholarly journals Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Jinfeng Liu ◽  
Huansheng Dong ◽  
Yong Zhang ◽  
Mingjun Cao ◽  
Lili Song ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Cholesterol Metabolism ◽  
Regulatory Element ◽  
Direct Bilirubin ◽  
Treatment Termination ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Abstract Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose and insulin tolerance tests were performed prior to, immediately and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR) and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin and increases in adiponectin and expression of SREBP-1, IR and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice.

scholarly journals Evidence for altered adipocyte function in polycystic ovary syndrome

2005 ◽  
Vol 152 (3) ◽  
pp. 389-394 ◽  
Author(s):  
E Carmina ◽  
F Orio ◽  
S Palomba ◽  
T Cascella ◽  
R A Longo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Polycystic Ovary Syndrome ◽  
Body Mass ◽  
Polycystic Ovary ◽  
Marked Change ◽  
Hormonal Changes ◽  
Ovary Syndrome ◽  
Strong Body ◽  
And Function

Background: Adipocytokines are produced by adipose tissue and have been thought to be related to insulin resistance and other health consequences. We measured leptin, adiponectin, and resistin simultaneously in women with polycystic ovary syndrome (PCOS) and age- and weight-matched controls. Our hypothesis was that these simultaneous measurements would help determine whether adipocytokine secretion is abnormal in PCOS independent of body mass and whether these levels are related to insulin resistance as well as other hormonal changes. Methods: Fifty-two women with PCOS and 45 normal ovulatory women who were age- and weight-matched were studied. Blood was obtained for adipocytokines (leptin, adiponectin, and resistin) as well as hormonal parameters and markers of insulin resistance as assessed by the quantitative insulin-sensitivity check index. Body mass index (BMI) was stratified into obese, overweight, and normal subgroups for comparisons between PCOS and controls. Results: Adiponectin was lower (P < 0.05) and resistin was higher (P < 0.05) while leptin was similar to matched controls. Breakdown of the groups into subgroups showed a strong body mass relationship for leptin with no changes in resistin although adiponectin was lower in PCOS, even controlling for BMI. In controls, leptin and adiponectin and leptin and resistin correlated (P < 0.05) but not in PCOS. In controls, all adipocytokines correlated with markers of insulin resistance but not in PCOS. Conclusions: When matched for BMI status, decreased adiponectin in PCOS represent the most marked change. This alteration may be the result of altered adipose tissue distribution and function in PCOS but no correlation with insulin resistance was found.

scholarly journals Beneficial Metabolic Effects of TREM2 in Obesity are Uncoupled from its Expression on Macrophages

2021 ◽  
Author(s):  
Omar Sharif ◽  
Julia Stefanie Brunner ◽  
Ana Korosec ◽  
Rui Martins ◽  
Alexander Jais ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Immune Cell ◽  
Metabolic Effects ◽  
Sphingolipid Metabolism ◽  
Protective Effects ◽  
Tissue Macrophage ◽  
Insulin Tolerance ◽  
Ceramide Synthesis

Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated ATM-expressed TREM2 promoted health. Here, we identified that in mice TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell-expressed TREM2 on health instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in TREM2’s systemic protective effects on metabolic health.

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