A reduced M1-like/M2-like ratio of macrophages in healthy adipose tissue expansion during SGLT2 inhibition

Miyachi, Yukihisa; Tsuchiya, Kyoichiro; Shiba, Kanako; Mori, Kentaro; Komiya, Chikara; Ogasawara, Naomi; Ogawa, Yoshihiro

doi:10.1038/s41598-018-34305-x

Cited by 45 publications

(22 citation statements)

References 44 publications

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“…The present study demonstrated that Ipra increased adipocyte size in abdominal PVAT in WD-induced obese and diabetic mice, which is consistent with our previous observation in Epi of diet-induced obese mice treated with SGLT2 inhibitors [19, 31, 32]. The adipocyte hypertrophy in abdominal PVAT accompanied a decrease of inflammation and fibrosis, which corresponded to “healthy adipose expansion” [33].…”

Section: Discussionsupporting

confidence: 91%

Ipragliflozin-induced adipose expansion inhibits cuff-induced vascular remodeling in mice

Mori

Tsuchiya

Nakamura

et al. 2019

Cardiovasc Diabetol

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Background: Perivascular adipose tissue (PVAT) plays a critical role in the pathogenesis of cardiovascular disease. It is unclear whether inhibition of sodium glucose cotransporter 2 (SGLT2) in subjects with type 2 diabetes (T2DM) could affect PVAT characters, and whether the SGLT2 inhibitors-induced changes of adipose tissue, especially the alternation of adipose tissue-derived secretory factors, affect vascular pathophysiology. Methods: Western-type diet (WD) fed wild-type mice were treated with or without an SGLT2 inhibitor ipragliflozin (Ipra) for 10 weeks. WEHI 274.1 and primary vascular smooth muscle cells were incubated with conditioned media (CM) of epididymal adipose tissue (Epi) or abdominal PVAT of Ipra-or vehicle-treated mice fed a WD. Epi of Ipra-or vehicle-treated mice fed a WD was implanted onto cuff-placed femoral arteries of apoE-deficient mice. Results: Ipra increased adipocyte size associated with decreased expression of pro-inflammatory and fibrosis-related genes in abdominal PVAT of WD-fed mice. Ipra also suppressed WD-induced macrophages accumulation, fibrosis, and adipocyte death in abdominal PVAT. In CM of abdominal PVAT from Ipra-treated mice, concentration of leptin was significantly lower than that from vehicle-treated mice. In vitro, migration of WEHI 274.1 and primary vascular smooth muscle cells were more enhanced by CM of Epi or abdominal PVAT from vehicle-treated mice than that from Ipratreated mice. Perivascular implantation of Epi from Ipra-treated mice to apolipoprotein E-deficient mice attenuated cuff-induced neointimal hyperplasia and vascular remodeling compared to that from vehicle-treated mice. Conclusions: The Ipra-induced changes of abdominal PVAT will lead to a better understanding of unveiled mechanisms by which SGLT2 inhibitors prevent cardiovascular complications in T2DM, and the development of new therapeutic strategies targeting PVAT.

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Section: Discussionsupporting

confidence: 91%

Ipragliflozin-induced adipose expansion inhibits cuff-induced vascular remodeling in mice

Mori

Tsuchiya

Nakamura

et al. 2019

Cardiovasc Diabetol

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“…Unlike in vitro conditions, macrophages usually develop mixed phenotypes in vivo in response to disease conditions, and they are difficult to separate using classical M1 or M2 surface markers. For example, it has been reported that macrophage populations display a mixed M1/M2 phenotype in obese patients 21 . The dynamic balance between M1-like and M2-like macrophages tightly controls the disease outcomes, suggesting that regulation of macrophage phenotype is a promising strategy for disease treatment.…”

Section: Macrophage Polarization and Functionsmentioning

confidence: 99%

Macrophage-derived extracellular vesicles: diverse mediators of pathology and therapeutics in multiple diseases

et al. 2020

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Macrophages (Mφ) are primary innate immune cells that exhibit diverse functions in response to different pathogens or stimuli, and they are extensively involved in the pathology of various diseases. Extracellular vesicles (EVs) are small vesicles released by live cells. As vital messengers, macrophage-derived EVs (Mφ-EVs) can transfer multiple types of bioactive molecules from macrophages to recipient cells, modulating the biological function of recipient cells. In recent years, Mφ-EVs have emerged as vital mediators not only in the pathology of multiple diseases such as inflammatory diseases, fibrosis and cancers, but also as mediators of beneficial effects in immunoregulation, cancer therapy, infectious defense, and tissue repair. Although many investigations have been performed to explore the diverse functions of Mφ-EVs in disease pathology and intervention, few studies have comprehensively summarized their detailed biological roles as currently understood. In this review, we briefly introduced an overview of macrophage and EV biology, and primarily focusing on current findings and future perspectives with respect to the pathological and therapeutic effects of Mφ-EVs in various diseases.

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“…For example, R-BHB, when given to isolated macrophages challenged with Streptococcus uberis , was shown to increase the expression of IL-1 β and IL-10 and the chemokines CXCL2 and CCL5 but had no effect on the expression of TNF- α and TGF- β [ 207 ]. In another report using isolated M1 peritoneal macrophages, R-BHB was shown to decrease the expression of IL-15, but not IL-1 β , TNF- α , or IL-6 [ 208 ]. In calf hepatocytes, R-BHB was shown to increase NF- κ B activity and the expression of IL-1 β , TNF- α , and IL-6 [ 209 ], while ketosis had similar effects in the liver of cows [ 210 ].…”

Section: Molecular Mechanisms Through Which R-bhb Inhibits Inflammmentioning

confidence: 99%

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Bradshaw

Seeds²,

Miller

et al. 2020

Oxidative Medicine and Cellular Longevity

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Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.

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A reduced M1-like/M2-like ratio of macrophages in healthy adipose tissue expansion during SGLT2 inhibition

Cited by 45 publications

References 44 publications

Ipragliflozin-induced adipose expansion inhibits cuff-induced vascular remodeling in mice

Ipragliflozin-induced adipose expansion inhibits cuff-induced vascular remodeling in mice

Macrophage-derived extracellular vesicles: diverse mediators of pathology and therapeutics in multiple diseases

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

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