Liver mitochondria and insulin resistance.

With a steadily increasing prevalence, insulin resistance (IR) is a major public health issue. This syndrome is defined as a set of metabolic dysfunctions associated with, or contributing to, a range of serious health problems. These disorders include type 2 diabetes, metabolic syndrome, obesity, and non-alcoholic steatohepatitis (NASH). According to the literature in the field, several cell types like β-cell, myocyte, hepatocyte and/or adipocyte, as well as related complex signaling environment involved in peripheral insulin sensitivity are believed to be central in this pathology. Because of the central role of the liver in the whole-body energy homeostasis, liver insulin sensitivity and its potential relationship with mitochondrial oxidative phosphorylation appear to be crucial. The following short review highlights how liver mitochondria could be implicated in IR and should therefore be considered as a specific therapeutic target in the future.

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Insulin resistance and whole body energy homeostasis in obese adolescents with fatty liver disease

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00017.2006 ◽

2006 ◽

Vol 291 (4) ◽

pp. E697-E703 ◽

Cited By ~ 75

Author(s):

Gianluca Perseghin ◽

Riccardo Bonfanti ◽

Serena Magni ◽

Guido Lattuada ◽

Francesco De Cobelli ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Energy Homeostasis ◽

Hdl Cholesterol ◽

Fat Content ◽

Whole Body ◽

Oral Glucose ◽

Obese Adolescents ◽

Glucose Challenge ◽

Body Energy

Obese adolescents are at risk of developing NAFLD and type 2 diabetes. We measured noninvasively the IHF content of obese adolescents to ascertain whether it is associated with insulin resistance and abnormal energy homeostasis. IHF content, whole body energy homeostasis, insulin sensitivity, and body composition were measured using localized hepatic 1H-MRS, indirect calorimetry, fasting-derived and 3-h-OGTT-derived surrogate indexes (HOMA2 and WBISI), and DEXA, respectively, in 54 obese adolescents (24 female and 30 male, age 13 ± 2 yr, BMI >99th percentile for their age and sex). NAFLD (defined as IHF content >5% wet weight) was found in 16 individuals (30%) in association with higher ALT ( P < 0.006), Hb A1c ( P = 0.021), trunk fat content ( P < 0.03), and lower HDL cholesterol ( P < 0.05). Individuals with NAFLD had higher fasting plasma glucose (89 ± 8 vs. 83 ± 9 mg/dl, P = 0.01) and impaired insulin sensitivity (HOMA2 and WBISI, P < 0.05). Meanwhile, parameters of insulin secretion were unaffected. Their reliance on fat oxidation in the fasting state was lower (RQ 0.83 ± 0.08 vs. 0.77 ± 0.05, P < 0.01), and their ability to suppress it during the oral glucose challenge was impaired ( P < 0.05) vs. those with normal IHF content. When controlling for trunk fat content, the correlation between IHF content and insulin sensitivity was weakened, whereas the correlation with fasting lipid oxidation was maintained. In conclusion, NAFLD is common in childhood obesity, and insulin resistance is present in association with increased trunk fat content. In contrast, the rearrangement of whole body substrate oxidation in these youngsters appeared to be an independent feature.

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Adipose Tissue Fibrosis in Obesity: Etiology and Challenges

Annual Review of Physiology ◽

10.1146/annurev-physiol-060721-092930 ◽

2021 ◽

Vol 84 (1) ◽

Author(s):

Geneviève Marcelin ◽

Emmanuel L. Gautier ◽

Karine Clément

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Molecular Mechanisms ◽

Whole Body ◽

Annual Review ◽

Publication Date ◽

Tissue Fibrosis ◽

Adipose Tissue Remodeling ◽

Metabolic Dysfunctions ◽

Body Energy

Obesity is a chronic and progressive process affecting whole-body energy balance and is associated with comorbidities development. In addition to increased fat mass, obesity induces white adipose tissue (WAT) inflammation and fibrosis, leading to local and systemic metabolic dysfunctions, such as insulin resistance (IR). Accordingly, limiting inflammation or fibrosis deposition may improve IR and glucose homeostasis. Although no targeted therapy yet exists to slow or reverse adipose tissue fibrosis, a number of findings have clarified the underlying cellular and molecular mechanisms. In this review, we highlight adipose tissue remodeling events shown to be associated with fibrosis deposition, with a focus on adipose progenitors involved in obesity-induced healthy as well as unhealthy WAT expansion. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways

Journal of Endocrinology ◽

10.1530/joe-13-0334 ◽

2013 ◽

Vol 220 (1) ◽

pp. 13-24 ◽

Cited By ~ 18

Author(s):

Anaies Nazarians-Armavil ◽

Jennifer A Chalmers ◽

Claire B Lee ◽

Wenqing Ye ◽

Denise D Belsham

Keyword(s):

Insulin Resistance ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Second Messengers ◽

Mrna Level ◽

Neuronal Cell ◽

Whole Body ◽

Cell Models ◽

Metabolic Hormones ◽

Body Energy

POMC neurons play a central role in the maintenance of whole-body energy homeostasis. This balance requires proper regulation of POMC neurons by metabolic hormones, such as insulin. However, the heterogeneous cellular population of the intact hypothalamus presents challenges for examining the molecular mechanisms underlying the potent anorexigenic effects of POMC neurons, and there is currently a complete lack of mature POMC neuronal cell models for study. To this end, we have generated novel, immortalized, adult-derived POMC-expressing/α-MSH-secreting cell models, mHypoA-POMC/GFP lines 1–4, representing the fluorescence-activated cell-sorted POMC population from primary POMC-eGFP mouse hypothalamus. The presence of Pomc mRNA in these cell lines was confirmed, and α-MSH was detected via immunofluorescence. α-MSH secretion in the mHypoA-POMC/GFP-1 was found to increase in response to 10 ng/ml ciliary neurotrophic factor (CNTF) or 10 nM insulin as determined by enzyme immunoassay. Further experiments using the mHypoA-POMC/GFP-1 cell line revealed that 10 ng/ml CNTF increases Pomc mRNA at 1 and 2 h after treatment, whereas insulin elicited an increase in Pomc mRNA level and decreases in insulin receptor (Insr (Ir)) mRNA level at 4 h. Furthermore, the activation of IR-mediated downstream second messengers was examined by western blot analysis, following the induction of cellular insulin resistance, which resulted in a loss of insulin-mediated regulation of Pomc and Ir mRNAs. The development of these immortalized neurons will be invaluable for the elucidation of the cellular and molecular mechanisms that underlie POMC neuronal function under normal and perturbed physiological conditions.

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Cellular Mechanism by Which Estradiol Protects Female Ovariectomized Mice From High-Fat Diet-Induced Hepatic and Muscle Insulin Resistance

Endocrinology ◽

10.1210/en.2012-1989 ◽

2013 ◽

Vol 154 (3) ◽

pp. 1021-1028 ◽

Cited By ~ 104

Author(s):

João Paulo G. Camporez ◽

François R. Jornayvaz ◽

Hui-Young Lee ◽

Shoichi Kanda ◽

Blas A. Guigni ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Protein Kinase ◽

High Fat Diet ◽

Estrogen Replacement Therapy ◽

Whole Body ◽

Estrogen Replacement ◽

High Fat ◽

Muscle Insulin Resistance ◽

Body Energy

Abstract Estrogen replacement therapy reduces the incidence of type 2 diabetes in postmenopausal women; however, the mechanism is unknown. Therefore, the aim of this study was to evaluate the metabolic effects of estrogen replacement therapy in an experimental model of menopause. At 8 weeks of age, female mice were ovariectomized (OVX) or sham (SHAM) operated, and OVX mice were treated with vehicle (OVX) or estradiol (E2) (OVX+E2). After 4 weeks of high-fat diet feeding, OVX mice had increased body weight and fat mass compared with SHAM and OVX+E2 mice. OVX mice displayed reduced whole-body energy expenditure, as well as impaired glucose tolerance and whole-body insulin resistance. Differences in whole-body insulin sensitivity in OVX compared with SHAM mice were accounted for by impaired muscle insulin sensitivity, whereas both hepatic and muscle insulin sensitivity were impaired in OVX compared with OVX+E2 mice. Muscle diacylglycerol (DAG), content in OVX mice was increased relative to SHAM and OVX+E2 mice. In contrast, E2 treatment prevented the increase in hepatic DAG content observed in both SHAM and OVX mice. Increases in tissue DAG content were associated with increased protein kinase Cϵ activation in liver of SHAM and OVX mice compared with OVX+E2 and protein kinase Cθ activation in skeletal muscle of OVX mice compared with SHAM and OVX+E2. Taken together, these data demonstrate that E2 plays a pivotal role in the regulation of whole-body energy homeostasis, increasing O2 consumption and energy expenditure in OVX mice, and in turn preventing diet-induced ectopic lipid (DAG) deposition and hepatic and muscle insulin resistance.

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Skeletal muscle AMP-activated protein kinase γ1H151R overexpression enhances whole body energy homeostasis and insulin sensitivity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00195.2015 ◽

2015 ◽

Vol 309 (7) ◽

pp. E679-E690 ◽

Cited By ~ 10

Author(s):

Milena Schönke ◽

Martin G. Myers ◽

Juleen R. Zierath ◽

Marie Björnholm

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Protein Kinase ◽

Transgenic Mice ◽

Energy Homeostasis ◽

Whole Body ◽

Α Subunit ◽

Peripheral Tissues ◽

Amp Activated Protein Kinase ◽

Body Energy

AMP-activated protein kinase (AMPK) is a major sensor of energy homeostasis and stimulates ATP-generating processes such as lipid oxidation and glycolysis in peripheral tissues. The heterotrimeric enzyme consists of a catalytic α-subunit, a β-subunit that is important for enzyme activity, and a noncatalytic γ-subunit that binds AMP and activates the AMPK complex. We generated a skeletal muscle Cre-inducible transgenic mouse model expressing a mutant γ1-subunit (AMPKγ1H151R), resulting in chronic AMPK activation. The expression of the predominant AMPKγ3 isoform in skeletal muscle was reduced in extensor digitorum longus (EDL) muscle (81–83%) of AMPKγ1H151R transgenic mice, whereas the abundance and phosphorylation of the AMPK target acetyl-CoA carboxylase was increased in tibialis anterior muscle. Glycogen content was increased 10-fold in gastrocnemius muscle. Whole body carbohydrate oxidation was increased by 11%, and whereas glucose tolerance was unaffected, insulin sensitivity was increased in AMPKγ1H151R transgenic mice. Furthermore, perigonadal white adipose tissue mass and serum leptin were reduced in female AMPKγ1H151R transgenic mice by 38 and 51% respectively. Conversely, in male AMPKγ1H151R transgenic mice, food intake was increased (14%), but body weight and body composition were unaltered, presumably because of increased energy expenditure. In conclusion, transgenic activation of skeletal muscle AMPKγ1 in this model plays an important sex-specific role in skeletal muscle metabolism and whole body energy homeostasis.

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Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance

Journal of Experimental Medicine ◽

10.1084/jem.20201416 ◽

2020 ◽

Vol 218 (3) ◽

Author(s):

Feng He ◽

Yanrui Huang ◽

Zhi Song ◽

Huanjiao Jenny Zhou ◽

Haifeng Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Energy Homeostasis ◽

Hepatic Insulin Resistance ◽

Whole Body ◽

Ros Generation ◽

Polyubiquitin Chains ◽

Adipose Inflammation ◽

Body Energy

White adipose tissues (WAT) play crucial roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to hepatic insulin resistance and type 2 diabetes mellitus (T2DM). However, the mechanisms underlying these alterations remain unknown. By analyzing the transcriptome landscape in human adipocytes based on available RNA-seq datasets from lean, obese, and T2DM patients, we reveal elevated mitochondrial reactive oxygen species (ROS) pathway and NF-κB signaling with altered fatty acid metabolism in T2DM adipocytes. Mice with adipose-specific deletion of mitochondrial redox Trx2 develop hyperglycemia, hepatic insulin resistance, and hepatic steatosis. Trx2-deficient WAT exhibited excessive mitophagy, increased inflammation, and lipolysis. Mechanistically, mitophagy was induced through increasing ROS generation and NF-κB–dependent accumulation of autophagy receptor p62/SQSTM1, which recruits damaged mitochondria with polyubiquitin chains. Importantly, administration of ROS scavenger or NF-κB inhibitor ameliorates glucose and lipid metabolic disorders and T2DM progression in mice. Taken together, this study reveals a previously unrecognized mechanism linking mitophagy-mediated adipose inflammation to T2DM with hepatic insulin resistance.

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Exercise and MEF2–HDAC interactions

Applied Physiology Nutrition and Metabolism ◽

10.1139/h07-082 ◽

2007 ◽

Vol 32 (5) ◽

pp. 852-856 ◽

Cited By ~ 21

Author(s):

Sean L. McGee

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Nuclear Export ◽

Energy Homeostasis ◽

Whole Body ◽

Positive Health ◽

Exercise Induced ◽

Amp Activated Protein Kinase ◽

Body Energy ◽

Skeletal Muscle Adaptations

Exercise increases the metabolic capacity of skeletal muscle, which improves whole-body energy homeostasis and contributes to the positive health benefits of exercise. This is, in part, mediated by increases in the expression of a number of metabolic enzymes, regulated largely at the level of transcription. At a molecular level, many of these genes are regulated by the class II histone deacetylase (HDAC) family of transcriptional repressors, in particular HDAC5, through their interaction with myocyte enhancer factor 2 transcription factors. HDAC5 kinases, including 5′-AMP-activated protein kinase and protein kinase D, appear to regulate skeletal muscle metabolic gene transcription by inactivating HDAC5 and inducing HDAC5 nuclear export. These mechanisms appear to participate in exercise-induced gene expression and could be important for skeletal muscle adaptations to exercise.

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Hepatokine ERAP1 impairs skeletal muscle insulin sensitivity via ADRB2/PKA pathway

10.21203/rs.3.rs-37586/v1 ◽

2020 ◽

Author(s):

Feifan Guo ◽

Yuguo Niu ◽

Haizhou Jiang ◽

Hanrui Yin ◽

Fenfen Wang ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Neutralizing Antibodies ◽

Leptin Receptor ◽

Whole Body ◽

C2c12 Myotubes ◽

Insulin Resistant ◽

Skeletal Muscle Insulin Sensitivity ◽

Pka Pathway

Abstract The current study aimed to investigate the role of endoplasmic reticulum aminopeptidase 1 (ERAP1), a novel hepatokine, in whole-body glucose metabolism. Here, we found that hepatic ERAP1 levels were increased in insulin-resistant leptin-receptor-mutated (db/db) and high-fat diet (HFD)-fed mice. Consistently, hepatic ERAP1 overexpression attenuated skeletal muscle (SM) insulin sensitivity, whereas knockdown ameliorated SM insulin resistance. Furthermore, serum and hepatic ERAP1 levels were positively correlated, and recombinant mouse ERAP1 or conditioned medium with high ERAP1 content (CM-ERAP1) attenuated insulin signaling in C2C12 myotubes, and CM-ERAP1 or HFD-induced insulin resistance was blocked by ERAP1 neutralizing antibodies. Mechanistically, ERAP1 reduced ADRB2 expression and interrupted ADRB2-dependent signaling in C2C12 myotubes. Finally, ERAP1 inhibition via global knockout or the inhibitor thimerosal improved insulin sensitivity. Together, ERAP1 is a hepatokine that impairs SM and whole-body insulin sensitivity, and its inhibition might provide a therapeutic strategy for diabetes, particularly for those with SM insulin resistance.

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Energy Metabolism of Bone

Toxicologic Pathology ◽

10.1177/0192623317737065 ◽

2017 ◽

Vol 45 (7) ◽

pp. 887-893 ◽

Cited By ~ 10

Author(s):

Katherine J. Motyl ◽

Anyonya R. Guntur ◽

Adriana Lelis Carvalho ◽

Clifford J. Rosen

Keyword(s):

Bone Remodeling ◽

Energy Homeostasis ◽

Bone Structure ◽

Bone Cells ◽

Bone Cell ◽

Whole Body ◽

Blood Calcium ◽

Micro Cracks ◽

Intimate Link ◽

Body Energy

Biological processes utilize energy and therefore must be prioritized based on fuel availability. Bone is no exception to this, and the benefit of remodeling when necessary outweighs the energy costs. Bone remodeling is important for maintaining blood calcium homeostasis, repairing micro cracks and fractures, and modifying bone structure so that it is better suited to withstand loading demands. Osteoclasts, osteoblasts, and osteocytes are the primary cells responsible for bone remodeling, although bone marrow adipocytes and other cells may also play an indirect role. There is a renewed interest in bone cell energetics because of the potential for these processes to be targeted for osteoporosis therapies. In contrast, due to the intimate link between bone and energy homeostasis, pharmaceuticals that treat metabolic disease or have metabolic side effects often have deleterious bone consequences. In this brief review, we will introduce osteoporosis, discuss how bone cells utilize energy to function, evidence for bone regulating whole body energy homeostasis, and some of the unanswered questions and opportunities for further research in the field.

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Treatment with an SSRI antidepressant restores hippocampo-hypothalamic corticosteroid feedback and reverses insulin resistance in low-birth-weight rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00606.2009 ◽

2010 ◽

Vol 298 (5) ◽

pp. E920-E929 ◽

Cited By ~ 23

Author(s):

Esben S. Buhl ◽

Thomas Korgaard Jensen ◽

Niels Jessen ◽

Betina Elfving ◽

Christian S. Buhl ◽

...

Keyword(s):

Insulin Resistance ◽

Birth Weight ◽

Insulin Sensitivity ◽

Low Birth Weight ◽

Mrna Expression ◽

Hpa Axis ◽

Whole Body ◽

Oral Glucose ◽

Red Muscle ◽

Hpa Axis Activity

Low birth weight (LBW) is associated with type 2 diabetes and depression, which may be related to prenatal stress and insulin resistance as a result of chronic hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We examined whether treatment with a selective serotonin reuptake inhibitor [escitalopram (ESC)] could downregulate HPA axis activity and restore insulin sensitivity in LBW rats. After 4–5 wk of treatment, ESC-exposed LBW (SSRI-LBW) and saline-treated control and LBW rats (Cx and LBW) underwent an oral glucose tolerance test or a hyperinsulinemic euglycemic clamp to assess whole body insulin sensitivity. Hepatic phospho enolpyruvate carboxykinase (PEPCK) mRNA expression and red skeletal muscle PKB Ser473phosphorylation were used to assess tissue-specific insulin sensitivity. mRNA expression of the hypothalamic mineralocorticoid receptor was fivefold upregulated in LBW ( P < 0.05 vs. Cx), accompanied by increased corticosterone release during restraint stress and total 24-h urinary excretion ( P < 0.05 vs. Cx), whole body insulin resistance ( P < 0.001 vs. Cx), and impaired insulin suppression of hepatic PEPCK mRNA expression ( P < 0.05 vs. Cx). Additionally, there was a tendency for reduced red muscle PKB Ser473phosphorylation. The ESC treatment normalized corticosterone secretion ( P < 0.05 vs. LBW), whole body insulin sensitivity ( P < 0.01) as well as postprandial suppression of hepatic mRNA PEPCK expression ( P < 0.05), and red muscle PKB Ser473phosphorylation ( P < 0.01 vs. LBW). We conclude that these data suggest that the insulin resistance and chronic HPA axis hyperactivity in LBW rats can be reversed by treatment with an ESC, which downregulates HPA axis activity, lowers glucocorticoid exposure, and restores insulin sensitivity in LBW rats.

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