Adipocyte-Specific Deficiency of De Novo Sphingolipid Biosynthesis Leads to Lipodystrophy and Insulin Resistance

Lee, Su Yeon; Lee, Hui Young; Song, Jae Yen; Kim, Goon Tae; Jeon, Suwon; Song, Yoo Jeong; Lee, Jae Sung; Hur, Jang Ho; Oh, Hyun Hee; Park, Shi Young; Shim, Soon Mi; Yoo, Hyun Joo; Lee, Byeong Cheol; Jiang, Xian Cheng; Choi, Cheol Soo; Park, Tae Sik

doi:10.2337/db16-1232

Cited by 54 publications

(41 citation statements)

References 45 publications

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“…Alexaki et al [48] showed that adipocyte-specific Sptlc1-knockout mice exhibit insulin resistance with agedependent loss of adipose tissue, increased macrophage infiltration and tissue fibrosis. Furthermore, Lee et al [49] showed that adipocyte-specific Sptlc2-knockout mice display systemic insulin resistance and hyperglycaemia. Taken together with our observations, chronic sphingolipid metabolism downregulation could thus potentially interfere with liver, muscle, adipose and beta cell function, contributing to type 2 diabetes onset.…”

Section: Discussionmentioning

confidence: 99%

The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

et al. 2019

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Aims/hypothesis Gestational diabetes mellitus (GDM) affects up to 20% of pregnancies, and almost half of the women affected progress to type 2 diabetes later in life, making GDM the most significant risk factor for the development of future type 2 diabetes. An accurate prediction of future type 2 diabetes risk in the early postpartum period after GDM would allow for timely interventions to prevent or delay type 2 diabetes. In addition, new targets for interventions may be revealed by understanding the underlying pathophysiology of the transition from GDM to type 2 diabetes. The aim of this study is to identify both a predictive signature and early-stage pathophysiology of the transition from GDM to type 2 diabetes. Methods We used a well-characterised prospective cohort of women with a history of GDM pregnancy, all of whom were enrolled at 6-9 weeks postpartum (baseline), were confirmed not to have diabetes via 2 h 75 g OGTT and tested anually for type 2 diabetes on an ongoing basis (2 years of follow-up). A large-scale targeted lipidomic study was implemented to analyse~1100 lipid metabolites in baseline plasma samples using a nested pair-matched case-control design, with 55 incident cases matched to 85 non-case control participants. The relationships between the concentrations of baseline plasma lipids and respective follow-up status (either type 2 diabetes or no type 2 diabetes) were employed to discover both a predictive signature and the underlying pathophysiology of the transition from GDM to type 2 diabetes. In addition, the underlying pathophysiology was examined in vivo and in vitro. Results Machine learning optimisation in a decision tree format revealed a seven-lipid metabolite type 2 diabetes predictive signature with a discriminating power (AUC) of 0.92 (87% sensitivity, 93% specificity and 91% accuracy). The signature was highly robust as it includes 45-fold cross-validation under a high confidence threshold (1.0) and binary output, which together minimise the chance of data overfitting and bias selection. Concurrent analysis of differentially expressed lipid metabolite pathways uncovered the upregulation of α-linolenic/linoleic acid metabolism (false discovery rate [FDR] 0.002) and fatty acid biosynthesis (FDR 0.005) and the downregulation of sphingolipid metabolism (FDR 0.009) as being strongly associated with the risk of developing future type 2 diabetes. Focusing specifically on sphingolipids, the downregulation of sphingolipid metabolism

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Section: Discussionmentioning

confidence: 99%

The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

et al. 2019

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“…Fbp2 deletion did not alter glucose metabolism during the feeding condition Because energy expenditure showed a different pattern between feeding and fasting periods, we further tested whether Fbp2 deficiency alters glucose metabolism in the fed condition. To measure in vivo whole-body and tissuespecific glucose fluxes under feeding-mimicking conditions where insulin and exogenous glucose are supplied, we performed hyperinsulinemic-euglycemic clamp studies on WT and Fbp2 KO mice as previously reported 23,30 . There was no difference in insulin-stimulated whole-body glucose utilization between Fbp2 KO and WT mice, as reflected by the identical glucose infusion rates needed to maintain euglycemia during the steady state ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The essential role of fructose-1,6-bisphosphatase 2 enzyme in thermal homeostasis upon cold stress

et al. 2020

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Skeletal muscle is a major organ for glucose disposal and thermogenesis. While hepatic fructose-1,6-bisphosphatase is well known as a key enzyme for gluconeogenesis, the role of muscle fructose-1,6-bisphosphatase 2 (Fbp2) in glucose disposal and thermogenesis is unknown. Here, using Fbp2 knockout (KO) mice, we assessed the physiological role of Fbp2 in energy and glucose metabolism and thermogenesis. In vivo assessments of energy metabolism, glucose metabolism, and thermogenesis were performed by indirect calorimetry, hyperinsulinemic-euglycemic clamp, and cold challenge studies, respectively. Under both feeding and fasting conditions, Fbp2 KO mice showed similar phenotypes regarding energy and glucose metabolism compared to wild-type (WT) mice. However, Fbp2 KO mice were severely intolerant to cold challenge under fasting conditions. Mechanistically, the cold-induced intramuscular conversion of lactate to glycogen (glyconeogenesis) is completely abolished in the KO muscle, which leads to a lack of glycogen source for thermogenesis in Fbp2 KO mice. The cold-intolerant phenotype of KO mice disappeared after feeding, and the KO mice were equally as cold tolerant as the WT mice and survived during the cold challenge for three weeks. Taken together, these data demonstrate that Fbp2 is essential for muscle thermogenesis by replenishing the intramuscular glycogen pool through glyconeogenesis when the exogenous glucose source is limited. These data imply the physiological importance of Fbp2 in thermal homeostasis and suggest a potential novel therapy targeted to increase glycogen replenishment upon cold stress.

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“…CER and SM, which are included as part of sphingolipids, have been demonstrated to play a substantial role in the development of a variety of diseases as important bioactive mediators. In adipose tissue, adipocyte-specific ablation of SPTLC2, a subunit of serine palmitoyltransferase that is an initial enzyme in sphingolipid biosynthesis, has been reported to increase CER[C24:1] content in adipose tissue of HFD-fed mice, and reduce adipose tissue mass with marked Pck1 downregulation 44 . In addition, the adipocyte-specific SPTLC2-knockout mice also accompanied hepatic steatosis, implying a mirror image phenotype of lipid deposition and content as the Ipra-treated mice in our study.…”

Section: Discussionmentioning

confidence: 99%

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

Miyachi

Tsuchiya

Shiba

et al. 2018

Sci Rep

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The adipose tissue includes various stromal cells, such as preadipocytes, endothelial cells, fibroblasts, and immune cells, which are involved in adipose tissue functions. We previously reported that, in obese mice, the sodium–glucose cotransporter 2 inhibitor ipragliflozin (Ipra) promoted the expansion of the epididymal adipose tissue (Epi) with increase of serum ketone body concentration. The Ipra-induced adipose tissue expansion did not deteriorate adipose inflammation, or systemic glucose/lipid metabolism, referred to as “healthy adipose tissue expansion.” Here we found that Ipra promoted healthy adipose tissue expansion with a reduced ratio of pro-inflammatory M1-like adipose tissue macrophages (ATMs) to anti-inflammatory M2-like ATMs. Ipra downregulated the gene expression of interleukin (IL)−15 (Il15) in stromal cells of Epi. IL-15 inhibited lipogenesis in 3T3-L1 cells associated with downregulation of the lipogenic gene. Ketone body β-hydroxybutyrate suppressed Il15 gene induction in M1-polarized cultured macrophages, and a ketogenic diet reproduced the adipose tissue expansion without deteriorating systemic glucose metabolism in mice. Our data indicate that the phenotypic switch of ATMs could mediate healthy adipose tissue expansion by treatment with Ipra, and it may offer new insights into the pathophysiological mechanisms of adipose tissue expansion.

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Adipocyte-Specific Deficiency of De Novo Sphingolipid Biosynthesis Leads to Lipodystrophy and Insulin Resistance

Cited by 54 publications

References 45 publications

The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

The essential role of fructose-1,6-bisphosphatase 2 enzyme in thermal homeostasis upon cold stress

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

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