Adiponectin is an adipocyte-derived hormone. Recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where the gene encoding adiponectin is located. Here we show that decreased expression of adiponectin correlates with insulin resistance in mouse models of altered insulin sensitivity. Adiponectin decreases insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. This effect results from increased expression of molecules involved in both fatty-acid combustion and energy dissipation in muscle. Moreover, insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. We conclude that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy. These data also indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.

The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity

Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.

The hormone resistin links obesity to diabetes

/pdf/transcriptional-regulation-of-adipogenesis-4blhib0oxp.pdf

Transcriptional regulation of adipogenesis

Obesity and the related disorders of dyslipidemia and diabetes (components of syndrome X) have become global health epidemics. Over the past decade, the elucidation of key regulators of energy balance and insulin signaling have revolutionized our understanding of fat and sugar metabolism and their intimate link. The three 'lipid-sensing' peroxisome proliferator-activated receptors (PPAR-alpha, PPAR-gamma and PPAR-delta) exemplify this connection, regulating diverse aspects of lipid and glucose homeostasis, and serving as bona fide therapeutic targets. With molecular underpinnings now in place, new pharmacologic approaches to metabolic disease and new questions are emerging.

PPARs and the complex journey to obesity

Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels (approximately 50, approximately 550, approximately 750 microM) on rates of glucose uptake, glycolysis (both with 3-3H-glucose), glycogen synthesis (determined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA concentration (from approximately 50 to approximately 750 microM) decreased glucose uptake in a dose-dependent fashion (from approximately 9 to approximately 4 mg/kg per min). The decrease was caused mainly (approximately 2/3) by a reduction in glycogen synthesis and to a lesser extent (approximately 1/3) by a reduction in CHO oxidation. We have identified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activity. It required high FFA concentration (approximately 750 microM), was associated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium (approximately 550 microM) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by approximately 50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level.

/pdf/mechanisms-of-fatty-acid-induced-inhibition-of-glucose-4174mdqw81.pdf

Mechanisms of fatty acid-induced inhibition of glucose uptake.

C-C chemokine receptor type 1 (CCR1) and its endogenous ligand, CCL5, participate in the pathogenesis of neuroinflammatory diseases. However, much remains unknown regarding CCL5/CCR1 signaling in blood-brain barrier (BBB) permeability after intracerebral hemorrhage (ICH).A total of 250 CD1 male mice were used and ICH was induced via autologous whole blood injection. Either Met-RANTES, a selective CCR1 antagonist, or Met-RANTES combined with a Rac1 CRISPR activator was administered to the mice 1 h after ICH. Post-ICH assessments included neurobehavioral tests, brain water content, BBB integrity, hematoma volume, Western blot, and immunofluorescence staining. The CCR1 ligand, rCCL5, and SRC CRISPR knockout in naïve mice were used to further elucidate detrimental CCL5/CCR1/SRC signaling.Brain endogenous CCR1 and CCL5 were upregulated after ICH in mice with a peak at 24 h, and CCR1 was expressed in endothelial cells, astrocytes, and neurons. Met-R treatment reduced brain edema and neurobehavioral impairment, as well as preserved BBB integrity and tight junction protein expression in ICH mice. Met-R treatment decreased expression of p-SRC, Rac1, albumin, and MMP9, but increased claudin-5, occludin, and ZO-1 tight junction proteins after ICH. These effects were regressed using the Rac1 CRISPR activator. Administration of rCCL5 in naïve mice increased expression of p-SRC, Rac1, albumin, and MMP9, but decreased levels of claudin-5, occludin, and ZO-1 tight junction proteins. These effects in naïve mice were reversed with SRC CRISPR (KO).Our findings demonstrate that CCR5 inhibition by Met-R improves neurological deficits after ICH by preserving BBB integrity through inhibiting CCR1/SRC/Rac1 signaling pathway in mice. Thus, Met-R has therapeutic potential in the management of ICH patients. 

https://fluidsbarrierscns.biomedcentral.com/counter/pdf/10.1186/s12987-022-00305-3

Met-RANTES preserves the blood–brain barrier through inhibiting CCR1/SRC/Rac1 pathway after intracerebral hemorrhage in mice

Background Excessive acetaminophen (APAP) use can lead to acute liver injury (ALI) by inducing endoplasmic reticulum stress (ERS). We previously found that pretreatment with the peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand rosiglitazone (RSG) alleviated ALI in APAP-treated mice. Objective To examine if RSG-mediated hepatoprotection is associated with ERS suppression. Methods Forty-eight male CD-1 mice were randomly divided into control, RSG, APAP 4 h, APAP 24 h, RSG + APAP 4 h, and RSG + APAP 24 h groups. The RSG and RSG + APAP groups received RSG (20 mg/kg) by gavage 48, 24, and 1 h before intraperitoneal injection of 300 mg/kg APAP, while the APAP group received APAP alone and the control group received only normal saline. Animals were sacrificed immediately (RSG and control groups), 4 h (APAP 4 h and RSG + APAP 4 h), or 24 h (APAP 24 h and RSG + APAP 24 h) post-APAP injection. Liver tissues were collected for hematoxylin-eosin staining, TUNEL staining, and Western blotting for ERS-associated proteins. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were also measured. A second cohort received APAP or RSG + APAP as described and were monitored for survival over one week. Results At 4 and 24 h following APAP injection alone, serum ALT and AST levels were significantly elevated, and central lobular necrosis of the liver was observed. Necrosis area reached 21.7% at 4 h and 32.1% at 24 h post-APAP, while apoptotic fractions reached 25.6% and 32.4%. Further, 50% of mice in the survival analysis cohort died within one week post-APAP. At 4 h post-APAP, the ERS marker glucose-regulated protein-78 (GRP78) and ERS-associated proteins pJNK, GRP78, p-eIF2α, pPERK, and pIRE were all significantly upregulated. Pretreatment with RSG significantly reduced serum ALT and AST, liver necrosis area, apoptosis rate, and expression of ERS-associated proteins compared to APAP alone, while increasing survival to 80%. Conclusions Rosiglitazone pretreatment can alleviate APAP-induced ALI by suppressing three branches of ERS signaling.

/pdf/rosiglitazone-protects-against-acetaminophen-induced-acute-13tuz0by.pdf

Rosiglitazone Protects against Acetaminophen-Induced Acute Liver Injury by Inhibiting Multiple Endoplasmic Reticulum Stress Pathways

Purpose: To investigate the role of tumor necrosis factor-induced protein 1 (TNFAIP1) and cAMPresponsive element binding protein (CREB)/nuclear factor-erythroid factor 2-related factor 2 (Nrf2) pathway in sevoflurane (SEV)-induced cognitive dysfunction. 
Methods: A SEV-induced cognitive dysfunction rat model was developed. Bcl-2, Bax, heme oxygenase-1, Nrf2, p-CREB, and CREB protein levels in rat hippocampal tissue were assessed by western blot. Learning and long-term memory were evaluated using Morris water maze test. Glutathione peroxidase, malondialdehyde, and superoxide dismutase levels in hippocampal tissue were measured by enzyme-linked immunosorbent assay (ELISA). The 2,7-dichlorodihydro-fluorescein diacetate fluorescent assay was used to measure reactive oxygen species, while TUNEL staining was used to assess neuronal cell apoptosis. 
Results: Knockdown of TNFAIP1 attenuated SEV-induced learning and long-term memory dysfunction (p < 0.005), oxidative stress (p < 0.005), apoptosis (p < 0.005), and inhibition of the CREB/Nrf2 signaling pathway. 
Conclusion: This study demonstrates that knockdown of TNFAIP1 alleviates SEV-induced cognitive dysfunction by reversing inhibition of the CREB/Nrf2 signaling pathway. 
Keywords: TNFAIP1; Postoperative cognitive dysfunction; Sevoflurane; cAMP-responsive element binding protein (CREB); Nuclear factor-erythroid factor 2-related factor 2 (Nrf2)

/pdf/knockdown-of-tnfaip1-mitigates-sevoflurane-induced-cognitive-2c50gclc.pdf

Knockdown of TNFAIP1 mitigates sevoflurane-induced cognitive dysfunction by activating CREB/Nrf2 pathway

This study aimed to explore the effect of naltrexone on the expression of lipid metabolism-related proteins in liver steatosis induced by endoplasmic reticulum stress in mice. Thirty inbred mice (C57BL/6J) were divided into three groups: group A (normal control group), group B (model control), and group C (naltrexone group). The male mice in group A were fed a regular diet, and the mice in groups B and C were fed a high-fat diet. Liver steatosis was observed by histopathological sections. Mouse liver (alanine aminotransferase (ALT) and triglyceride (TC)) content (glucose regulatory protein (GRP78), endoplasmic reticulum transmembrane protein kinase-1α (IRE-1α), C/EBP source protein (CHOP), cysteine-containing aspartate proteolytic enzyme 12 (caspase-12), B lymphoma-2 (Bcl-2), and cell death mediator (Bim)) was detected. Compared with group A, bodyweight, fat weight, ALT, TG, and hepatic steatosis were significantly increased in B and C groups (P < 0.05); compared with group B, group C showed a significant decrease in bodyweight, fat weight, ALT, TG, and hepatic steatosis (P < 0.05). Compared with group A, the expression levels of GRP78, IRE-1α, CHOP, caspase-12, and Bim in liver tissue of groups B and C mice were increased. Bcl-2 decreased (P < 0.05). Compared with group B and group C after naltrexone intervention, the expression levels of GRP78, IRE-1α, CHOP, caspase-12, and Bim decreased significantly, and Bcl-2 increased significantly (P < 0.05). Naltrexone can effectively reduce bodyweight and adipose tissue accumulation, reduce liver fat lesions, improve the expression of lipid metabolism-related proteins and endoplasmic reticulum stress, reduce liver lipid synthesis, and protect liver cells.

/pdf/effects-of-naltrexone-on-expression-of-lipid-metabolism-1r4nsht1.pdf

Effects of Naltrexone on Expression of Lipid Metabolism-Related Proteins in Liver Steatosis Induced by Endoplasmic Reticulum Stress in Mice

The thiazolidinedione class of insulin-sensitizing, antidiabetic drugs interacts with peroxisome proliferator–activated receptor γ (PPAR-γ). To gain insight into the role of this nuclear receptor in insulin resistance and diabetes, we conducted metabolic studies in the PPAR-γ gene knockout mouse model. Because homozygous PPAR-γ–null mice die in development, we studied glucose metabolism in mice heterozygous for the mutation (PPAR-γ+/– mice). We identified no statistically significant differences in body weight, basal glucose, insulin, or FFA levels between the wild-type (WT) and PPAR-γ+/– groups. Nor was there a difference in glucose excursion between the groups of mice during oral glucose tolerance test, but insulin concentrations of the WT group were greater than those of the PPAR-γ+/– group, and insulin-induced increase in glucose disposal rate was significantly increased in PPAR-γ+/– mice. Likewise, the insulin-induced suppression of hepatic glucose production was significantly greater in the PPAR-γ+/– mice than in the WT mice. Taken together, these results indicate that — counterintuitively — although pharmacological activation of PPAR-γ improves insulin sensitivity, a similar effect is obtained by genetically reducing the expression levels of the receptor.

/pdf/improved-insulin-sensitivity-in-mice-heterozygous-for-ppar-g-1rh62yfixn.pdf

Improved insulin-sensitivity in mice heterozygous for PPAR-γ deficiency

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