| 1. |
- Lager, Susanne, 1978, et al.
(författare)
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Perinatal lack of maternal IL-6 promotes increased adiposity during adulthood in mice.
- 2011
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 152:4, s. 1336-46
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Tidskriftsartikel (refereegranskat)abstract
- The perinatal environment appears important in establishing metabolic phenotypes in adulthood. Mice deficient in IL-6 (IL-6(-/-)) tend to develop mature-onset obesity, but it is unknown whether perinatal exposure to IL-6 produced by the dam influences the metabolism of adult offspring. To address this issue, we monitored IL-6(-/-) offspring of IL-6(-/-) or IL-6(+/-) dams, as well as wild-type (WT) mice. At adult age, IL-6(-/-) mice weighed significantly more and had more body fat than WT mice, regardless of maternal genotype, and had lower insulin sensitivity. This phenotype was more pronounced in IL-6(-/-) offspring of IL-6(-/-) dams, because they gained weight significantly faster than IL-6(-/-) offspring of IL-6(+/-) dams and had more body fat and higher serum leptin levels at an earlier age. The leptin content was 2-fold higher in milk from IL-6(-/-) than WT dams. However, cross-fostering IL-6(-/-) mice with WT dams did not alter body weight, body composition, or adipocyte size at adult age compared with IL-6(-/-) mice fostered by IL-6(-/-) dams. Conversely, WT mice fostered by IL-6(-/-) dams weighed significantly more than those fostered by WT dams and had more body fat, larger adipocytes, and altered hypothalamic gene expression. We conclude that body fat of adult mice can be increased by perinatal exposure to factors affected by lack of maternal IL-6.
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| 2. |
- Xia, Ying, et al.
(författare)
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Knockout of STE20-type kinase TAOK3 does not attenuate diet-induced NAFLD development in mice
- 2023
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Ingår i: Molecular Medicine. - 1076-1551. ; 29:1
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveNon-alcoholic fatty liver disease (NAFLD), the primary hepatic consequence of obesity, is affecting about 25% of the global adult population. The aim of this study was to examine the in vivo role of STE20-type protein kinase TAOK3, which has been previously reported to regulate hepatocellular lipotoxicity in vitro, in the development of NAFLD and systemic insulin resistance in the context of obesity.MethodsTaok3 knockout mice and wild-type littermates were challenged with a high-fat diet. Various in vivo tests were performed to characterize the whole-body metabolism. NAFLD progression in the liver, and lipotoxic damage in adipose tissue, kidney, and skeletal muscle were compared between the genotypes by histological assessment, immunofluorescence microscopy, protein and gene expression profiling, and biochemical assays. Intracellular lipid accumulation and oxidative/ER stress were analyzed in cultured human and mouse hepatocytes where TAOK3 was knocked down by small interfering RNA. The expression of TAOK3-related STE20-type kinases was quantified in different organs from high-fat diet-fed Taok3-/- and wild-type mice.ResultsTAOK3 deficiency had no impact on body weight or composition, food consumption, locomotor activity, or systemic glucose or insulin homeostasis in obese mice. Consistently, Taok3-/- mice and wild-type littermates developed a similar degree of high-fat diet-induced liver steatosis, inflammation, and fibrosis, and we detected no difference in lipotoxic damage of adipose tissue, kidney, or skeletal muscle when comparing the two genotypes. In contrast, the silencing of TAOK3 in vitro markedly suppressed ectopic lipid accumulation and metabolic stress in mouse and human hepatocytes. Interestingly, the hepatic mRNA abundance of several TAOK3-related kinases, which have been previously implicated to increase the risk of NAFLD susceptibility, was significantly elevated in Taok3-/-vs. wild-type mice.ConclusionsIn contrast to the in vitro observations, genetic deficiency of TAOK3 in mice failed to mitigate the detrimental metabolic consequences of chronic exposure to dietary lipids, which may be partly attributable to the activation of liver-specific compensation response for the genetic loss of TAOK3 by related STE20-type kinases.
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| 3. |
- An, Y. A., et al.
(författare)
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Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity
- 2019
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Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 1:12, s. 1243-57
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial function in white adipose tissue (WAT) is an important yet understudied aspect of adipocyte biology. Here, we report a role for amyloid precursor protein (APP) in compromising WAT mitochondrial function through a high-fat diet (HFD)-induced, unconventional mis-localization to mitochondria that further promotes obesity. In humans and mice, obese conditions induce substantial APP production in WAT and APP enrichment in mitochondria. Mechanistically, HFD-induced dysregulation of signal recognition particle subunit 54c is responsible for the mis-targeting of APP to adipocyte mitochondria. Mis-localized APP blocks the protein import machinery, leading to mitochondrial dysfunction in WAT. Mice overexpressing adipocyte-specific and mitochondria-targeted APP display increased body mass and reduced insulin sensitivity, along with dysfunctional WAT, owing to a dramatic hypertrophic program in adipocytes. Elimination of adipocyte APP rescues HFD-impaired mitochondrial function with considerable protection from weight gain and systemic metabolic deficiency. Our data highlight an important role for APP in modulating WAT mitochondrial function and obesity-associated metabolic dysfunction.
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| 4. |
- Anderberg, Rozita H, 1976, et al.
(författare)
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Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:4, s. 1062-1073
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT2A) and 5-HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT2A, but surprisingly not the 5-HT2C, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation.
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| 5. |
- Bauzá-Thorbrügge, Marco, et al.
(författare)
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Adipocyte-specific ablation of the Ca2+ pump SERCA2 impairs whole-body metabolic function and reveals the diverse metabolic flexibility of white and brown adipose tissue.
- 2022
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Ingår i: Molecular metabolism. - : Elsevier BV. - 2212-8778. ; 63
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Tidskriftsartikel (refereegranskat)abstract
- Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) transports Ca2+ from the cytosol into the endoplasmic retitculum (ER) and is essential for appropriate regulation of intracellular Ca2+ homeostasis. The objective of this study was to test the hypothesis that SERCA pumps are involved in the regulation of white adipocyte hormone secretion and other aspects of adipose tissue function and that this control is disturbed in obesity-induced type-2 diabetes.SERCA expression was measured in isolated human and mouse adipocytes as well as in whole mouse adipose tissue by Western blot and RT-qPCR. To test the significance of SERCA2 in adipocyte functionality and whole-body metabolism, we generated adipocyte-specific SERCA2 knockout mice. The mice were metabolically phenotyped by glucose tolerance and tracer studies, histological analyses, measurements of glucose-stimulated insulin release in isolated islets, and gene/protein expression analyses. We also tested the effect of pharmacological SERCA inhibition and genetic SERCA2 ablation in cultured adipocytes. Intracellular and mitochondrial Ca2+ levels were recorded with dual-wavelength ratio imaging and mitochondrial function was assessed by Seahorse technology.We demonstrate that SERCA2 is downregulated in white adipocytes from patients with obesity and type-2 diabetes as well as in adipocytes from diet-induced obese mice. SERCA2-ablated adipocytes display disturbed Ca2+ homeostasis associated with upregulated ER stress markers and impaired hormone release. These adipocyte alterations are linked to mild lipodystrophy, reduced adiponectin levels, and impaired glucose tolerance. Interestingly, adipocyte-specific SERCA2 ablation leads to increased glucose uptake in white adipose tissue while the glucose uptake is reduced in brown adipose tissue. This dichotomous effect on glucose uptake is due to differently regulated mitochondrial function. In white adipocytes, SERCA2 deficiency triggers an adaptive increase in fibroblast growth factor 21 (FGF21), increased mitochondrial uncoupling protein 1 (UCP1) levels, and increased oxygen consumption rate (OCR). In contrast, brown SERCA2 null adipocytes display reduced OCR despite increased mitochondrial content and UCP1 levels compared to wild type controls.Our data suggest causal links between reduced white adipocyte SERCA2 levels, deranged adipocyte Ca2+ homeostasis, adipose tissue dysfunction and type-2 diabetes.
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| 6. |
- Bauzá-Thorbrügge, Marco, et al.
(författare)
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NRF2 is essential for adaptative browning of white adipocytes.
- 2023
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Ingår i: Redox biology. - : Elsevier. - 2213-2317. ; 68
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Tidskriftsartikel (refereegranskat)abstract
- White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes.
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| 7. |
- Benrick, Anna, 1979, et al.
(författare)
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Adiponectin protects against development of metabolic disturbances in a PCOS mouse model
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:34
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Tidskriftsartikel (refereegranskat)abstract
- Adiponectin, together with adipocyte size, is the strongest factor associated with insulin resistance in women with polycystic ovary syndrome (PCOS). This study investigates the causal relationship between adiponectin levels and metabolic and reproductive functions in PCOS. Prepubertal mice overexpressing adiponectin from adipose tissue (APNtg), adiponectin knockouts (APNko), and their wild-type (WT) littermate mice were continuously exposed to placebo or dihydrotestosterone (DHT) to induce PCOS-like traits. As expected, DHT exposure led to reproductive dysfunction, as judged by continuous anestrus, smaller ovaries with a decreased number of corpus luteum, and an increased number of cystic/atretic follicles. A two-way between-groups analysis showed that there was a significant main effect for DHT exposure, but not for genotype, indicating adiponectin does not influence follicle development. Adiponectin had, however, some protective effects on ovarian function. Similar to in many women with PCOS, DHT exposure led to reduced adiponectin levels, larger adipocyte size, and reduced insulin sensitivity in WTs. APNtg mice remained metabolically healthy despite DHT exposure, while APNko-DHT mice were even more insulin resistant than their DHT-exposed littermate WTs. DHT exposure also reduced the mRNA expression of genes involved in metabolic pathways in gonadal adipose tissue of WT and APNko, but this effect of DHT was not observed in APNtg mice. Moreover, APNtg-DHT mice displayed increased pancreatic mRNA levels of insulin receptors, Pdx1 and Igf1R, suggesting adiponectin stimulates beta cell viability/hyperplasia in the context of PCOS. In conclusion, adiponectin improves metabolic health but has only minor effects on reproductive functions in this PCOS-like mouse model.
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| 8. |
- Benrick, Anna, 1979, et al.
(författare)
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Elevated interlukin-6 levels as a consequence, not the cause of obesity and insulin resistance
- 2013
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Ingår i: Interleukin-6: Genetics, Clinical Applications and Role in Disease. - : Nova Science Publishers, Inc.. - 9781624175923 ; , s. 197-210
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Bokkapitel (refereegranskat)abstract
- Several population-based studies have reported that serum interleukin-6 (IL-6) levels are positively correlated with obesity and insulin resistance. This has lead to the hypothesis of a causal relationship between elevated IL-6 levels and insulin resistance. This notion is further strengthened by the observation that obesity is associated with a chronic low-grade inflammation in adipose tissue, which is postulated to be causal in the development of insulin resistance and type-2 diabetes. A recent study of weight gain demonstrates however that insulin resistance develops even in the absence of a significant signs of adipose inflammation. This suggests that inflammation in adipose tissue occurs subsequent to peripheral insulin resistance in humans. More and more data also supports the hypothesis that increased adiposity in itself, independent of the increased IL-6 levels, is a predictor of diabetes risk. IL-6 levels tend to also increase with age and since the incidence of insulin resistance and type-2 diabetes also increases with age, this could explain some of the observed correlations. Taken together, the above studies provide an association of metabolic disorder with IL-6, but not causation. An emerging concept is that IL-6 appears to have different effects on different tissues, and the effects depend on whether the IL-6 levels are acutely or chronically elevated. Given the opposing views of the impact of IL-6 on glucose homeostasis, many investigations have aimed at clarifying the effects of IL-6 on insulin action. A recent study shows that IL-6, either released from skeletal muscle or adipose tissue, induces GLP-1 release, leading to insulin secretion, improved beta-cell function and glycemic control. Still, the causal relationships between IL-6, obesity and type-2 diabetes remain a matter of debate. This review summarizes the current data on IL-6, supporting an association, but not a causative relationship, between IL-6 and metabolic disturbances. © 2013 Nova Science Publishers, Inc. All rights reserved.
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| 9. |
- Benrick, Anna, 1979, et al.
(författare)
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Interleukin-6 gene knockout influences energy balance regulating peptides in the hypothalamic paraventricular and supraoptic nuclei.
- 2009
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Ingår i: Journal of neuroendocrinology. - : Wiley. - 1365-2826 .- 0953-8194. ; 21:7, s. 620-8
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin (IL)-6 is a pro-inflammatory cytokine that also affects metabolic function because IL-6 depleted (IL-6(-/-)) mice develop late-onset obesity. IL-6 appears to act in the central nervous system, presumably in the hypothalamus, to increase energy expenditure that appears to involve stimulation of the sympathetic nervous system. In the present study, we explored possible central mechanisms for the effects exerted by IL-6 on body fat. Therefore, we measured the effects of IL-6 depletion in IL-6(-/-) mice on expression of key hypothalamic peptide genes involved in energy balance by the real time polymerase chain reaction. Additionally, co-localisation between such peptides and IL-6 receptor alpha was investigated by immunohistochemistry. IL-6 deficiency decreased the expression of several peptides found in the paraventricular nucleus (PVN), which is a nucleus that has been attributed an adipostatic function. For example, corticotrophin-releasing hormone (CRH), which is reported to stimulate the sympathetic nervous system, was decreased by 40% in older IL-6(-/-) mice. Oxytocin, which is reported to prevent obesity, was also decreased in older IL-6(-/-) animals, as was arginine vasopressin (AVP). The IL-6 receptor alpha was abundantly expressed in the PVN, but also in the supraoptic nucleus, and was shown to be co-expressed to a high extent with CRH, AVP, oxytocin and thyrotrophin-releasing hormone. These data indicate that depletion of endogenous IL-6, a body fat suppressing cytokine, is associated with the decreased expression of CRH and oxytocin (i.e. energy balance regulating peptides) as well as AVP in the PVN. Because IL-6 receptor alpha is co-expressed with CRH, oxytocin and AVP, IL-6 could stimulate the expression of these peptides directly.
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| 10. |
- Benrick, Anna, 1979, et al.
(författare)
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Interleukin-6 mediates exercise-induced increase in insulin sensitivity in mice.
- 2012
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Ingår i: Experimental physiology. - : Wiley. - 1469-445X .- 0958-0670. ; 97:11 SI, s. 1224-1235
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-6 (IL-6) is released from working skeletal muscle during exercise. We investigated the acute and the long-term beneficial effects of IL-6 on exercise-induced glucose uptake in skeletal muscle and insulin sensitivity. The acute effect on exercise-induced glucose uptake was measured in IL-6 deficient (-/-) mice and wild type controls using a tracer technique. There was no difference in serum disappearance of 3H-2-deoxyglucose after a bolus dose of exercise between IL-6 -/- and wild type mice (13565 ± 426 vs. 14343 ± 1309 dpm*min/ml, p=0.5). The glucose uptake rate in the EDL muscle was however lower in IL-6 -/- compared to wildtype mice (398 ± 44 vs. 657 ± 41 nmol/g/min, p<0.01). In the long-term study, we monitored insulin sensitivity, serum retinol-binding protein-4 (RBP-4) levels, running activity, food intake, body weight and body composition in IL-6 -/- and wild type mice on a high-fat diet (HFD), with or without access to running wheels. In sedentary IL-6 -/- and wild type mice, HFD decreased insulin sensitivity (glucose AUC increased about 20% during an insulin tolerance test (ITT), p<0.05 for both genotypes vs. baseline) and led to a 30% increase in serum RBP-4 levels (p <0.01 for both genotypes vs. baseline). Wild type runners were protected against these effects of HFD and maintained their baseline insulin sensitivity and serum RBP-4 levels. In contrast, IL-6 -/- mice did not, to the same extent as wild types, benefit from running. IL-6 -/- runners had a similar decrease in insulin sensitivity as their sedentary littermates (glucose AUC during an ITT in runners vs. sedentary IL-6-/- HFD mice: 312 ± 14 vs. 340 ± 22 mmol*min/L, p=0.4) and displayed a 14% increase in serum RBP-4 as compared to baseline levels (p<0.01). Our results indicate that endogenous IL-6 contributes to the exercise-induced increase in insulin sensitivity, but only plays a minor role for glucose uptake into skeletal muscle during exercise.
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