Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance.

In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.

Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity.

Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance.

NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids.

Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies.

GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects.

Omega-3 fatty acids (omega-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here, we show that the G protein-coupled receptor 120 (GPR120) functions as an omega-3 FA receptor/sensor. Stimulation of GPR120 with omega-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high-fat diet with or without omega-3 FA supplementation. The omega-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional omega-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation.

Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism.

Dysregulation of lipid metabolism in individual tissues leads to systemic disruption of insulin action and glucose metabolism. Utilizing quantitative lipidomic analyses and mice deficient in adipose tissue lipid chaperones aP2 and mal1, we explored how metabolic alterations in adipose tissue are linked to whole-body metabolism through lipid signals. A robust increase in de novo lipogenesis rendered the adipose tissue of these mice resistant to the deleterious effects of dietary lipid exposure. Systemic lipid profiling also led to identification of C16:1n7-palmitoleate as an adipose tissue-derived lipid hormone that strongly stimulates muscle insulin action and suppresses hepatosteatosis. Our data reveal a lipid-mediated endocrine network and demonstrate that adipose tissue uses lipokines such as C16:1n7-palmitoleate to communicate with distant organs and regulate systemic metabolic homeostasis.

Artificial Intelligence in Chemistry: Current Trends and Future Directions.

The application of artificial intelligence (AI) to chemistry has grown tremendously in recent years. In this Review, we studied the growth and distribution of AI-related chemistry publications in the last two decades using the CAS Content Collection. The volume of both journal and patent publications have increased dramatically, especially since 2015. Study of the distribution of publications over various chemistry research areas revealed that analytical chemistry and biochemistry are integrating AI to the greatest extent and with the highest growth rates. We also investigated trends in interdisciplinary research and identified frequently occurring combinations of research areas in publications. Furthermore, topic analyses were conducted for journal and patent publications to illustrate emerging associations of AI with certain chemistry research topics. Notable publications in various chemistry disciplines were then evaluated and presented to highlight emerging use cases. Finally, the occurrence of different classes of substances and their roles in AI-related chemistry research were quantified, further detailing the popularity of AI adoption in the life sciences and analytical chemistry. In summary, this Review offers a broad overview of how AI has progressed in various fields of chemistry and aims to provide an understanding of its future directions.

Recent Changes in the Scaffold Diversity of Organic Chemistry As Seen in the CAS Registry.

A large set of organic compounds extracted from the CAS Registry is analyzed to study recent changes in structural diversity. The diversity is characterized using the framework content of the compounds; the framework of a molecule is the scaffold consisting of all its ring systems and all the chain fragments connecting them. The compounds are partitioned based on their year of first report in the literature, which allows framework occurrence frequencies to be compared across a 10-year interval. The results are consistent with a process in which frameworks with the greatest frequency of use in the past are the most likely to be used again, but it is also found that the frequency ordering changes over time. These fluctuations in ordering are attributed to stochastic factors, scientific and economic, that can affect how chemical space is explored. Framework diversity is found to have increased over time despite the extensive reuse of a relatively small number of frameworks; this increase is due to the large number of new frameworks. The long tail of the framework distribution, composed of frameworks that occur in few compounds or only one compound, is found to be a large and growing part of framework space.

Individual serum saturated fatty acids and markers of chronic subclinical inflammation: the Insulin Resistance Atherosclerosis Study.

Recent evidence has documented distinct effects of individual saturated FAs (SFAs) on cardiometabolic outcomes, with potential protective effects from odd- and very long-chain SFAs (VLSFAs). Cross-sectional and prospective associations of individual serum SFAs (12:0, 14:0, 15:0, 16:0, 18:0, 20:0, 22:0, and total SFA) with proinflammatory biomarkers and adiponectin were investigated in 555 adults from the IRAS. Principal component analysis (PCA) of proinflammatory markers yielded three clusters: principal component (PC) 1: fibrinogen, white cell count, C-reactive protein; PC 2: plasminogen activator inhibitor-1 (PAI-1), TNF-α, IL-18; PC 3: IL-6 and IL-8. Cross-sectional analyses on proinflammatory PCs and adiponectin, and prospective analyses on 5 year PAI-1 and fibrinogen concentrations were conducted with multiple regression. Total SFA and 16:0 were positively associated with PC 1 and PC 2, and negatively associated with adiponectin. The 14:0 was positively associated with PC 1 and negatively associated with adiponectin. In contrast, 15:0, 20:0, and 22:0 were negatively associated with PC 2, and 20:0 and 22:0 were positively associated with adiponectin. The 18:0 was negatively associated with PC 3. Prospectively, 15:0, 18:0, 20:0, and 22:0 were negatively associated with 5 year PAI-1 concentrations. The results demonstrate that individual SFAs have distinct roles in subclinical inflammation, highlighting the unique metabolic impacts of individual SFAs.

Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity.

The endoplasmic reticulum (ER) is the main site of protein and lipid synthesis, membrane biogenesis, xenobiotic detoxification and cellular calcium storage, and perturbation of ER homeostasis leads to stress and the activation of the unfolded protein response. Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity. However, the mechanisms that lead to chronic ER stress in a metabolic context in general, and in obesity in particular, are not understood. Here we comparatively examined the proteomic and lipidomic landscape of hepatic ER purified from lean and obese mice to explore the mechanisms of chronic ER stress in obesity. We found suppression of protein but stimulation of lipid synthesis in the obese ER without significant alterations in chaperone content. Alterations in ER fatty acid and lipid composition result in the inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) activity and ER stress. Correcting the obesity-induced alteration of ER phospholipid composition or hepatic Serca overexpression in vivo both reduced chronic ER stress and improved glucose homeostasis. Hence, we established that abnormal lipid and calcium metabolism are important contributors to hepatic ER stress in obesity.

Dual actions of a novel bifunctional compound to lower glucose in mice with diet-induced insulin resistance.

Docosahexaenoic acid (DHA 22:6n-3) and salicylate are both known to exert anti-inflammatory effects. This study investigated the effects of a novel bifunctional drug compound consisting of DHA and salicylate linked together by a small molecule that is stable in plasma but hydrolyzed in the cytoplasm. The components of the bifunctional compound acted synergistically to reduce inflammation mediated via nuclear factor κB in cultured macrophages. Notably, oral administration of the bifunctional compound acted in two distinct ways to mitigate hyperglycemia in high-fat diet-induced insulin resistance. In mice with diet-induced obesity, the compound lowered blood glucose by reducing hepatic insulin resistance. It also had an immediate glucose-lowering effect that was secondary to enhanced glucagon-like peptide-1 (GLP-1) secretion and abrogated by the administration of exendin(9-39), a GLP-1 receptor antagonist. These results suggest that the bifunctional compound could be an effective treatment for individuals with type 2 diabetes and insulin resistance. This strategy could also be employed in other disease conditions characterized by chronic inflammation.

Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues.

Sirt1 is a NAD(+)-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. To assess this idea, we generated Sirt1 neuron-specific knockout (SINKO) mice. On both standard chow and HFD, SINKO mice were more insulin sensitive than Sirt1(f/f) mice. Thus, SINKO mice had lower fasting insulin levels, improved glucose tolerance and insulin tolerance, and enhanced systemic insulin sensitivity during hyperinsulinemic euglycemic clamp studies. Hypothalamic insulin sensitivity of SINKO mice was also increased over controls, as assessed by hypothalamic activation of PI3K, phosphorylation of Akt and FoxO1 following systemic insulin injection. Intracerebroventricular injection of insulin led to a greater systemic effect to improve glucose tolerance and insulin sensitivity in SINKO mice compared with controls. In line with the in vivo results, insulin-induced AKT and FoxO1 phosphorylation were potentiated by inhibition of Sirt1 in a cultured hypothalamic cell line. Mechanistically, this effect was traced to a reduced effect of Sirt1 to directly deacetylate and repress IRS-1 function. The enhanced central insulin signaling in SINKO mice was accompanied by increased insulin receptor signal transduction in liver, muscle, and adipose tissue. In summary, we conclude that neuronal Sirt1 negatively regulates hypothalamic insulin signaling, leading to systemic insulin resistance. Interventions that reduce neuronal Sirt1 activity have the potential to improve systemic insulin action and limit weight gain on an obesigenic diet.

Diets high in protein or saturated fat do not affect insulin sensitivity or plasma concentrations of lipids and lipoproteins in overweight and obese adults.

BACKGROUND: Previous human studies reported inconsistent effects of dietary protein and branched-chain amino acids (BCAAs) on insulin action and glucose metabolism. Similarly, it is unclear whether saturated fat (SF) intake influences these metabolic variables. OBJECTIVE: The objective of this study was to test the effects of high [30% of energy (%E)] vs. moderate (20%E) intakes of protein (primarily whey) on insulin action and lipid and lipoprotein concentrations in the context of both high (15%E) and low (7%E) SF diets. METHODS: The study was conducted as a randomized controlled trial in 158 overweight and obese men and women. After a 4-wk baseline diet [55%E carbohydrate, 15%E protein, 30%E fat (7%E SF)], participants were randomly assigned to 4 wk of either the baseline diet or 1 of 4 test diets containing 35%E carbohydrate and either 20%E or 30%E protein and either 7%E or 15%E SF. Frequently sampled i.v. glucose tolerance tests were administered after each dietary period. RESULTS: Other than significantly higher fasting glucose concentrations for high vs. moderate protein intakes with a low-fat diet (difference ± SE: 0.47 ± 0.14 mmol/L; P = 0.001), there were no significant effects of dietary protein or SF on glucose metabolism, plasma insulin, or concentrations of lipids and lipoproteins. Changes in plasma BCAAs across all diets were negatively correlated with changes in the metabolic clearance rate of insulin (ρ = -0.18, P = 0.03) and positively correlated with changes in the acute insulin response to glucose (ρ = 0.15, P = 0.05). CONCLUSIONS: These findings suggest that short-term intake of BCAAs can influence insulin dynamics. However, in this group of overweight and obese individuals, neither high protein nor SF intake affected insulin sensitivity or plasma concentrations of lipids and lipoproteins. This trial was registered at clinicaltrials.gov as NCT00508937.

High fish plus fish oil intake is associated with slightly reduced risk of venous thromboembolism: the Tromsø Study.

Current knowledge of the effect of fish consumption on risk of venous thromboembolism (VTE) is scarce and diverging. Therefore, the purpose of the present study was to investigate the impact of fish consumption and fish oil supplements on the risk of VTE in a population-based cohort. Weekly intake of fish for dinner and intake of fish oil supplements during the previous year were registered in 23,621 persons aged 25-97 y who participated in the Tromsø Study from 1994 to 1995. Incident VTE events were registered throughout follow-up (31 December 2010). Cox-regression models were used to calculate HRs for VTE, adjusted for age, body mass index, sex, triglycerides, HDL cholesterol, physical activity, and education level. During a median of 15.8 y of follow-up there were 536 incident VTE events. High fish consumption was associated with a slightly reduced risk of VTE. Participants who ate fish ≥3 times/wk had 22% lower risk of VTE than those who consumed fish 1-1.9 times/wk (multivariable HR: 0.78; 95% CI: 0.60, 1.01; P = 0.06). The addition of fish oil supplements strengthened the inverse association with risk of VTE. Participants who consumed fish ≥3 times/wk who additionally used fish oil supplements had 48% lower risk than those who consumed fish 1-1.9 times/wk but did not use fish oil supplements (HR: 0.52; 95% CI: 0.34, 0.79; P = 0.002). In conclusion, a high weekly intake (≥3 times/wk) of fish was associated with a slightly reduced risk of VTE, and the addition of fish oil supplements strengthened the inverse effect.

Promoting atherosclerosis in type 1 diabetes through the selective activation of arachidonic acid and PGE(2) production.

Type 1 diabetics harbor a greatly elevated risk for progressive atherosclerosis and cardiovascular events, but the mechanistic basis for this phenomenon is not entirely clear. Although this link is likely to involve many factors, the specific activation of a lipid-driven inflammatory phenotype in monocytes and macrophages of people with type 1 diabetes is an attractive causal mechanism, due to the ability of inflamed macrophages to exacerbate plaque deposition, expansion, and instability.

Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans.

Alterations in fat metabolism, in particular elevated plasma concentrations of free fatty acids and triglycerides (TG), have been implicated in the pathogenesis of Type 2 diabetes, obesity, and cardiovascular disease. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a member of the large family of membrane-bound O-acyltransferases, catalyzes the final step in triacylglycerol formation. In the intestine, DGAT1 is one of the acyltransferases responsible for the reesterficiation of dietary TG. Following a single dose of a selective pharmacological inhibitor of DGAT1, PF-04620110, a dose-dependent inhibition of TG and vitamin A absorption postprandially was demonstrated in rodents and human subjects. In C57/BL6J mice, acute DGAT1 inhibition alters the temporal and spatial pattern of dietary lipid absorption. To understand the impact of DGAT1 inhibition on enterocyte lipid metabolism, lipomic profiling was performed in rat intestine and plasma as well as human plasma. DGAT1 inhibition causes an enrichment of polyunsaturated fatty acids within the TG class of lipids. This pharmacological intervention gives us insight as to the role of DGAT1 in human dietary lipid absorption.

Reciprocal metabolic perturbations in the adipose tissue and liver of GPIHBP1-deficient mice.

OBJECTIVE: Gpihbp1-deficient (Gpihbp1-/-) mice lack the ability to transport lipoprotein lipase to the capillary lumen, resulting in mislocalization of lipoprotein lipase within tissues, defective lipolysis of triglyceride-rich lipoproteins, and chylomicronemia. We asked whether GPIHBP1 deficiency and mislocalization of catalytically active lipoprotein lipase would alter the composition of triglycerides in adipose tissue or perturb the expression of lipid biosynthetic genes. We also asked whether perturbations in adipose tissue composition and gene expression, if they occur, would be accompanied by reciprocal metabolic changes in the liver. METHODS AND RESULTS: The chylomicronemia in Gpihbp1-/- mice was associated with reduced levels of essential fatty acids in adipose tissue triglycerides and increased expression of lipid biosynthetic genes. The liver exhibited the opposite changes: increased levels of essential fatty acids in triglycerides and reduced expression of lipid biosynthetic genes. CONCLUSIONS: Defective lipolysis in Gpihbp1-/- mice causes reciprocal metabolic perturbations in adipose tissue and liver. In adipose tissue, the essential fatty acid content of triglycerides is reduced and lipid biosynthetic gene expression is increased, whereas the opposite changes occur in the liver.

Avoiding problems with hydrogen misplacement in reporting crystal structures.

Intermolecular hydrogen bonding is an integral part of many crystal structures. Hydrogen bonding sometimes results in one-, two- or three-dimensional supramolecular assemblies, a common feature of which is positional disorder of H atoms related to space-group symmetry. Yet some reported structures fail to include all possible donor­acceptor close contacts, or to seek H-atom electron densities associated with apparent D-H∙∙∙A trios, while some H-atom positions violate principles of chemistry or crystal physics. Modern diffraction equipment and sophisticated computing systems provide high-quality data; thus, failure to characterize and report fully an accurate, complete and physically correct hydrogen-bonding model should not be acceptable. We illustrate the relevant issues with three published examples in the hope of slowing the proliferation of these problems, with the scientifically desirable goal of improving the accuracy of crystallographic models while also providing improved search keys for information retrieval.

1-[3-(Naphthalen-1-yl)phen-yl]naphthal-ene.

The title compound, C(26)H(18), consists of a benzene ring with meta-substituted 1-naphthalene substituents, which are essentially planar (r.m.s. deviation = 0.039 and 0.027 Å). The conformation is mixed syn/anti, with equivalent torsion angles about the benzene-naphthalene bonds of 121.46 (11) and 51.58 (14)°.

2-[3-(Naphthalen-2-yl)phen-yl]naph-thal-ene.

The title compound, C(26)H(18), consists of a benzene ring with meta-substituted 2-naphthalene substituents, which are essentially planar [r.m.s. deviations = 0.022 (1) and 0.003 (1) Å]. The conformation is syn, with equivalent torsion angles about the benzene-naphthalene bonds of -36.04 (13) and +34.14 (13)°. The mol-ecule has quasi-C(s) mol-ecular symmetry.

Lung cancer resection in patients with underlying usual interstitial pneumonia: a meta-analysis.

OBJECTIVE: Patients with lung cancer with underlying idiopathic pulmonary fibrosis and usual interstitial pneumonia (UIP) pattern on CT represent a very high-risk group in terms of postoperative UIP acute exacerbations (AEs) and in-hospital mortality. We sought to investigate the outcomes in these patients. METHODS: We carried out a meta-analysis, searching four international databases from 1 January 1947 to 27 April 2022, for studies in any language reporting on the acute postoperative outcomes of patients with lung cancer undergoing surgical resection with underlying UIP (the primary outcome). Random effects meta-analyses (DerSimonian and Laird) were conducted. We analysed the difference in incidence of postoperative AE as well as the difference in long-term overall survival among subpopulations. These were stratified by the extent of surgical resection, with meta-regression testing (uniivariate and multivariate) according to the stage of disease, operative decision making and country of origin. This study was registered with PROSPERO (CRD42022319245). RESULTS: The overall incidence of AE of UIP postoperatively from 10 studies (2202 patients) was 14.6% (random effects model, 95% CI 9.8 to 20.1, I2=74%). Sublobar resection was significantly associated with a reduced odds of postoperative AE (OR 0.521 (fixed effects model), 95% CI 0.339 to 0.803, p=0.0031, I2=0%). The extent of resection was not significantly associated with overall survival following lung cancer resection in UIP patients (HR for sublobar resection 0.978 (random effects model), 95% CI 0.521 to 1.833, p=0.9351, I2=71%). CONCLUSIONS: With appropriate implementation of perioperative measures such as screening for high-risk cases, appropriate use of steroids, antifibrotics and employing sublobar resection in select cases, the risk of local recurrence versus in-hospital mortality from AEUIP can be balanced and long-term survival can be achieved in a super-selected group of patients. Further investigation in the form of a randomised study is warranted.