Obesity increases the risk of cancer. Increased levels of hormones (such as oestrogen, insulin, insulin-like growth factor, and leptin), free fatty acid-induced production of reactive oxygen species, ...an altered intestinal microbiome and chronic inflammation are known to be associated with an increased cancer risk in obese subjects. However, the mechanism underlying the connection between obesity and cancer development remains elusive. Here, we show that a high-fat diet (HFD) promotes tumour initiation/progression and induces a phenotypic switch from PD-1
CD8
non-exhausted T cells to PD-1
CD8
exhausted T cells in a murine breast cancer model. While PD-1
CD8
non-exhausted T cells predominated in the mammary glands of normal diet (ND)-fed mice, PD-1
CD8
exhausted T cells accumulated in the developing tumours of HFD-fed mice. Gene expression profiles indicated that PD-1
CD8
T cells expressed higher levels of the tumour-trophic gene Opn and lower levels of the cytotoxic genes Ifng and Gzmb than did PD-1
CD8
T cells. Our study provides a possible mechanistic linkage between obesity and cancer.
Nicotinamide phosphoribosyltransferase (NAMPT), the key NAD+ biosynthetic enzyme, has two different forms, intra- and extracellular (iNAMPT and eNAMPT), in mammals. However, the significance of ...eNAMPT secretion remains unclear. Here we demonstrate that deacetylation of iNAMPT by the mammalian NAD+-dependent deacetylase SIRT1 predisposes the protein to secretion in adipocytes. NAMPT mutants reveal that SIRT1 deacetylates lysine 53 (K53) and enhances eNAMPT activity and secretion. Adipose tissue-specific Nampt knockout and knockin (ANKO and ANKI) mice show reciprocal changes in circulating eNAMPT, affecting hypothalamic NAD+/SIRT1 signaling and physical activity accordingly. The defect in physical activity observed in ANKO mice is ameliorated by nicotinamide mononucleotide (NMN). Furthermore, administration of a NAMPT-neutralizing antibody decreases hypothalamic NAD+ production, and treating ex vivo hypothalamic explants with purified eNAMPT enhances NAD+, SIRT1 activity, and neural activation. Thus, our findings indicate a critical role of adipose tissue as a modulator for the regulation of NAD+ biosynthesis at a systemic level.
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•SIRT1 deacetylates iNAMPT and enhances eNAMPT activity and secretion in adipocytes•eNAMPT from adipose tissue affects hypothalamic NAD+/SIRT1 and physical activity•A NAMPT-neutralizing antibody suppresses eNAMPT and hypothalamic NAD+ in vivo•eNAMPT enhances NAD+/SIRT1 and neural activity in ex vivo hypothalamic explants
Yoon et al. shed light on the two forms of the NAD+ biosynthetic enzyme, intra- and extracellular NAMPT. SIRT1-mediated deacetylation of iNAMPT promotes its extracellular secretion from adipocytes. eNAMPT, in turn, affects NAD+/SIRT1 signaling in the hypothalamus, with effects on physical activity, implicating adipose tissue as a systemic NAD+ modulator.
Adipose tissue resident macrophages have important roles in the maintenance of tissue homeostasis and regulate insulin sensitivity for example by secreting pro-inflammatory or anti-inflammatory ...cytokines. Here, we show that M2-like macrophages in adipose tissue regulate systemic glucose homeostasis by inhibiting adipocyte progenitor proliferation via the CD206/TGFβ signaling pathway. We show that adipose tissue CD206
cells are primarily M2-like macrophages, and ablation of CD206
M2-like macrophages improves systemic insulin sensitivity, which was associated with an increased number of smaller adipocytes. Mice genetically engineered to have reduced numbers of CD206
M2-like macrophages show a down-regulation of TGFβ signaling in adipose tissue, together with up-regulated proliferation and differentiation of adipocyte progenitors. Our findings indicate that CD206
M2-like macrophages in adipose tissues create a microenvironment that inhibits growth and differentiation of adipocyte progenitors and, thereby, control adiposity and systemic insulin sensitivity.Adipose tissue contains macrophages that can influence both local and systemic metabolism via the secretion of cytokines. Here, Nawaz et al. report that M2-like macrophages, present in adipose tissue, create a microenvironment that inhibits proliferation of adipocyte progenitors due to the secretion of TGF-β1.
Background
Skeletal muscle is mainly responsible for insulin‐stimulated glucose disposal. Dysfunction in skeletal muscle metabolism especially during obesity contributes to the insulin resistance. ...Astaxanthin (AX), a natural antioxidant, has been shown to ameliorate hepatic insulin resistance in obese mice. However, its effects in skeletal muscle are poorly understood. The current study aimed to investigate the molecular target of AX in ameliorating skeletal muscle insulin resistance.
Methods
We fed 6‐week‐old male C57BL/6J mice with normal chow (NC) or NC supplemented with AX (NC+AX) and high‐fat‐diet (HFD) or HFD supplemented with AX for 24 weeks. We determined the effect of AX on various parameters including insulin sensitivity, glucose uptake, inflammation, kinase signaling, gene expression, and mitochondrial function in muscle. We also determined energy metabolism in intact C2C12 cells treated with AX using the Seahorse XFe96 Extracellular Flux Analyzer and assessed the effect of AX on mitochondrial oxidative phosphorylation and mitochondrial biogenesis.
Results
AX‐treated HFD mice showed improved metabolic status with significant reduction in blood glucose, serum total triglycerides, and cholesterol (p< 0.05). AX‐treated HFD mice also showed improved glucose metabolism by enhancing glucose incorporation into peripheral target tissues, such as the skeletal muscle, rather than by suppressing gluconeogenesis in the liver as shown by hyperinsulinemic–euglycemic clamp study. AX activated AMPK in the skeletal muscle of the HFD mice and upregulated the expressions of transcriptional factors and coactivator, thereby inducing mitochondrial remodeling, including increased mitochondrial oxidative phosphorylation component and free fatty acid metabolism. We also assessed the effects of AX on mitochondrial biogenesis in the siRNA‐mediated AMPK‐depleted C2C12 cells and showed that the effect of AX was lost in the genetically AMPK‐depleted C2C12 cells. Collectively, AX treatment (i) significantly ameliorated insulin resistance and glucose intolerance through regulation of AMPK activation in the muscle, (ii) stimulated mitochondrial biogenesis in the muscle, (iii) enhanced exercise tolerance and exercise‐induced fatty acid metabolism, and (iv) exerted antiinflammatory effects via its antioxidant activity in adipose tissue.
Conclusions
We concluded that AX treatment stimulated mitochondrial biogenesis and significantly ameliorated insulin resistance through activation of AMPK pathway in the skeletal muscle.
Astaxanthin (AX), a lipid-soluble pigment belonging to the xanthophyll carotenoids family, has recently garnered significant attention due to its unique physical properties, biochemical attributes, ...and physiological effects. Originally recognized primarily for its role in imparting the characteristic red-pink color to various organisms, AX is currently experiencing a surge in interest and research. The growing body of literature in this field predominantly focuses on AXs distinctive bioactivities and properties. However, the potential of algae-derived AX as a solution to various global environmental and societal challenges that threaten life on our planet has not received extensive attention. Furthermore, the historical context and the role of AX in nature, as well as its significance in diverse cultures and traditional health practices, have not been comprehensively explored in previous works. This review article embarks on a comprehensive journey through the history leading up to the present, offering insights into the discovery of AX, its chemical and physical attributes, distribution in organisms, and biosynthesis. Additionally, it delves into the intricate realm of health benefits, biofunctional characteristics, and the current market status of AX. By encompassing these multifaceted aspects, this review aims to provide readers with a more profound understanding and a robust foundation for future scientific endeavors directed at addressing societal needs for sustainable nutritional and medicinal solutions. An updated summary of AXs health benefits, its present market status, and potential future applications are also included for a well-rounded perspective.
Because oxidative stress promotes insulin resistance in obesity and type 2 diabetes, it is crucial to find effective antioxidant for the purpose of decreasing this threat. In this study, we explored ...the effect of astaxanthin, a carotenoid antioxidant, on insulin signaling and investigated whether astaxanthin improves cytokine- and free fatty acid-induced insulin resistance in vitro. We examined the effect of astaxanthin on insulin-stimulated glucose transporter 4 (GLUT4) translocation, glucose uptake, and insulin signaling in cultured rat L6 muscle cells using plasma membrane lawn assay, 2-deoxyglucose uptake, and Western blot analysis. Next, we examined the effect of astaxanthin on TNFα- and palmitate-induced insulin resistance. The amount of reactive oxygen species generated by TNFα or palmitate with or without astaxanthin was evaluated by dichlorofluorescein staining. We also compared the effect of astaxanthin on insulin signaling with that of other antioxidants, α-lipoic acid and α-tocopherol. We observed astaxanthin enhanced insulin-stimulated GLUT4 translocation and glucose uptake, which was associated with an increase in insulin receptor substrate-1 tyrosine and Akt phosphorylation and a decrease in c-Jun N-terminal kinase (JNK) and insulin receptor substrate-1 serine 307 phosphorylation. Furthermore, astaxanthin restored TNFα- and palmitate-induced decreases in insulin-stimulated GLUT4 translocation or glucose uptake with a concomitant decrease in reactive oxygen species generation. α-Lipoic acid enhanced Akt phosphorylation and decreased ERK and JNK phosphorylation, whereas α-tocopherol enhanced ERK and JNK phosphorylation but had little effect on Akt phosphorylation. Collectively these findings indicate astaxanthin is a very effective antioxidant for ameliorating insulin resistance by protecting cells from oxidative stress generated by various stimuli including TNFα and palmitate.
Aims/Introduction
This study aimed to identify the clinical factors affecting postoperative residual pancreatic β‐cell function, as assessed by the C‐peptide index (CPI), and to investigate the ...association between perioperative CPI and the status of diabetes management after pancreatectomy.
Materials and Methods
The associations between perioperative CPI and clinical background, including surgical procedures of pancreatectomy, were analyzed in 47 patients who underwent pancreatectomy, and were assessed for pre‐and postoperative CPI. The association between perioperative CPI and glycemic control after pancreatectomy was investigated.
Results
The low postoperative CPI group (CPI <0.7) had longer duration of diabetes (17.5 ± 14.5 vs 5.5 ± 11.0 years, P = 0.004), a higher percentage of sulfonylurea users (41.7 vs 8.7%, P = 0.003) and a greater number of drug categories used for diabetes treatment (1.9 ± 1.1 vs 0.8 ± 0.8, P <0.001) than did the high postoperative CPI group. Postoperative CPI was higher (1.4 ± 1.2 vs 0.7 ± 0.6, P = 0.039) in patients with low glycosylated hemoglobin (<7.0%) at 6 months after pancreatectomy; preoperative (2.0 ± 1.5 vs 0.7 ± 0.5, P = 0.012) and postoperative CPI (2.5 ± 1.4 vs 1.4 ± 1.1, P = 0.020) were higher in non‐insulin users than in insulin users at 6 months after surgery.
Conclusions
The duration of diabetes and preoperative diabetes treatment were associated with residual pancreatic β‐cell function after pancreatectomy. Furthermore, perioperative β‐cell function as assessed by CPI was associated with diabetes management status after pancreatectomy.
Perioperative beta cell function as assessed by CPI in patients who underwent pancreatectomy was associated with glycemic control and the requirement of insulin therapy after pancreatectomy.
Aims/Introduction
Endogenous insulin secretion could be recovered by improving hyperglycemia in patients with type 2 diabetes. This study aimed to investigate the association between short‐term ...recovery of insulin secretion during hospitalization and clinical background or future glycemic control in patients with type 2 diabetes.
Materials and Methods
A total of 127 patients with type 2 diabetes were included. The recovery of endogenous insulin secretion was determined using the following indices: index A: fasting C‐peptide index (CPI) at discharge – fasting CPI on admission; index B: postprandial CPI at discharge – postprandial CPI on admission; and index C: Δ C‐peptide immunoreactivity (CPR) (postprandial CPR − fasting CPR) at discharge – ΔCPR on admission. We examined the associations of each index with clinical background and future glycemic control measured by glycosylated hemoglobin and continuous glucose monitoring.
Results
Using index A and B, the age was significantly younger, whereas BMI and visceral fat area were significantly higher in the high‐recovery group than in the low‐recovery group. Changes in glycosylated hemoglobin levels were significantly greater at 6 and 12 months in the high‐recovery group in the analysis of index C. The receiver operating characteristic curve analysis identified the index B and index C as indicators to predict glycosylated hemoglobin <7.0% at 6 months after discharge. Furthermore, index C was positively correlated with the time in the target glucose range, and inversely correlated with the standard deviation of glucose at 3 and 12 months after discharge.
Conclusions
Short‐term recovery of insulin secretion in response to a meal during hospitalization, evaluated with the index‐C, might predict future glycemic control.
We investigated the association between short‐term recovery of insulin secretion during hospitalization and clinical background or future glycemic control in patients with type 2 diabetes. According to our results, short‐term recovery of insulin secretion in response to a meal during hospitalization might predict future glycemic control.
Aims/Introduction
Fragmented QRS (fQRS) on electrocardiography is a marker of myocardial fibrosis and myocardial scar formation. This study aimed to clarify the relationship of fQRS with diabetes ...mellitus and metabolic syndrome (MetS) in Japanese patients.
Materials and Methods
Approximately 702 individuals who had a routine health checkup at the Hokuriku Health Service Association (Toyama, Japan) in October 2014 were enrolled and categorized into one of the following four groups based on MetS and diabetes mellitus status: with diabetes mellitus (+) MetS+ (164 participants); diabetes mellitus+ without MetS (Mets−; 103 participants); diabetes mellitus− MetS+ (133 participants); and diabetes mellitus− MetS− (302 participants). fQRS was assessed using the results of electrocardiography.
Results
The prevalence of fQRS was statistically higher in patients with diabetes mellitus+ MetS+ (37%) and diabetes mellitus+ MetS− (35%), than those with diabetes mellitus− MetS+ (14%) or diabetes mellitus− MetS− (10%; P < 0.0001). Significant differences were observed between the fQRS(+) and fQRS(–) groups for age, sex, waist circumference, heart rate, hypertension, hemoglobin A1c, total cholesterol, MetS and diabetes mellitus. The area under the receiver operating characteristic curve for traditional risk factors and diabetes mellitus was 0.72 (P = 0.0007, 95% confidence interval 0.67–0.76), and for traditional risk factors and MetS it was 0.67 (P = 0.28, 95% confidence interval 0.62–0.72). Patients with diabetes mellitus had more than threefold higher likelihood of showing fQRS (odds ratio 3.41; 95% confidence interval 2.25–5.22; P < 0.0001) compared with the reference group without diabetes mellitus, after adjusting for age, sex, dyslipidemia, hypertension and waist circumference.
Conclusions
fQRS was observed more frequently in diabetes mellitus patients than in MetS and control individuals. Diabetes mellitus was the most significant determinant for fQRS among MetS and other traditional metabolic risk factors.
Fragmented QRS was observed more frequently in patients with diabetes mellitus than in metabolic syndrome and control individuals. Diabetes mellitus was the most significant determinant for fragmented QRS among metabolic syndrome and other traditional metabolic risk factors.
An immune‐related adverse event is a new disease entity that occurs after the introduction and extensive use of anticancer immune agents, such as anti‐programmed cell death protein 1 (PD‐1) or ...anti‐programmed death ligand 1 (PD‐L1) antibodies. HLA deoxyribonucleic acid typing detected by polymerase chain reaction sequenced‐based typing methods were as follows: ...clinical features strongly suggested the patient had type 2 diabetes with middle‐aged onset, obesity and family history of type 2 diabetes.
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