Macrophage LAMTOR1 Deficiency Prevents Dietary Obesity and Insulin Resistance Through Inflammation-Induced Energy Expenditure.

Here, we studied the metabolic function of LAMTOR1 from macrophages using LAMTOR1 macrophage-specific knockout (MKO) mice. LAMTOR1 MKO mice showed resistance to high-fat diet (HFD)-induced obesity, lipid steatosis, and glucose metabolic disorders, with elevated levels of pro-inflammatory cytokines. The energy expenditure, oxygen consumption, and CO2 production increased significantly in HFD-fed MKO vs. wild-type (WT) mice. HE and immunohistochemistry staining showed a remarkable CD68+ Kupffer cell accumulation in the liver. Additionally, flow cytometry revealed that the proportion of macrophages and monocytes increased significantly in the liver of MKO mice. Of note, these macrophages were probably derived from the bone marrow since the proportion of CD11b+ cells as well as the proliferative activity was also increased in the context of femoral bone marrow cells. In addition, the Kupffer cells of both WT and KO mice were double-positive for the M1 (CD86) and M2 (CD206) markers. However, the expression of both M1 and M2 macrophage-related genes was increased in the liver of HFD-fed KO mice. Murine primary hepatocytes and Kupffer cells were further isolated and incubated with oleic acid for 24 h. The glucose output of primary hepatocytes from MKO mice was not affected. However, decreased lipid tolerance was observed in LAMTOR1-deficient Kupffer cells. Overall, our results suggest that LAMTOR1 deficiency in macrophages prevents obesity and metabolic disorders via the accumulation of Kupffer cells in the liver and the consequent hyper-inflammation and increased energy expenditure. Therefore, our results provide a new perspective for macrophage-derived LAMTOR1 in the context of systemic metabolism.

Serum metabolic signatures of subclinical atherosclerosis in patients with type 2 diabetes mellitus: a preliminary study.

AIMS: Atherosclerotic cardiovascular disease remains the leading cause of death among patients with diabetes. Early identification of subclinical atherosclerosis is essential for the management of diabetic patients. This study aimed to characterize serum metabolic signatures associated with carotid intima-media thickness (C-IMT), a proxy of subclinical atherosclerosis, in patients with type 2 diabetes mellitus (T2DM). METHODS: After 1:1 matching by sex, age, body mass index, glycated haemoglobin A1c, and other clinical parameters, a total of 462 T2DM patients were enrolled, consisting of 231 patients with C-IMT of ≥ 1 mm (abnormal C-IMT) and 231 patients with C-IMT of < 1 mm (normal C-IMT). C-IMT was assessed using ultrasonography. The serum metabolic profiling of fasting blood samples was performed using liquid chromatography-tandem triple quadrupole mass spectrometer coupled with the multivariate and univariate statistical analysis. RESULTS: Patients with abnormal C-IMT had significantly higher deoxycholic acid (DCA) and taurodeoxycholic acid (TDCA) levels, and lower levels of taurocholic acid (TCA) than those with normal C-IMT. Conditional logistic regression analysis revealed that per 1-standard deviation increase of DCA, TDCA and TCA were significantly associated with 64.7% (95% CI: 1.234-2.196) and 38.5% (95% CI: 1.124-1.706) higher, and 26.8% (95% CI: 0.597-0.897) lower risk of abnormal C-IMT, after adjustment of confounders. The addition of DCA, TCA, or DCA × TDCA/TCA ratio significantly improved the discrimination of abnormal C-IMT over traditional risk factors. CONCLUSIONS: Serum bile acids may be potential biomarkers for subclinical atherosclerosis in T2DM patients, which needs further confirmation.

The association between serum growth differentiation factor 15 levels and lower extremity atherosclerotic disease is independent of body mass index in type 2 diabetes.

BACKGROUND: Clinical and basic investigations have indicated a significant association between circulating growth differentiation factor 15 (GDF15) and cardiovascular disease; however, the relationship between GDF15 and lower extremity atherosclerotic disease (LEAD) has been less studied. The present study aimed to explore the association between GDF15 and LEAD in Chinese patients with type 2 diabetes mellitus (T2DM). Considering that obesity is an important factor associated with circulating GDF15 levels, whether the relationship between serum GDF15 levels and LEAD is affected by body mass index (BMI) was also analysed. METHODS: A total of 376 hospitalized T2DM patients were enrolled (161 with LEAD and 215 without LEAD). A sandwich enzyme-linked immunosorbent assay was used to detect the serum GDF15 levels. The femoral intima-media thickness (F-IMT) and LEAD were assessed by ultrasonography. RESULTS: Patients with LEAD had significantly higher serum GDF15 levels than those without LEAD, regardless of whether their BMI was < 25 kg/m2 or ≥ 25 kg/m2 (both P < 0.05). Serum GDF15 levels were independently positively related to the F-IMT (standardized ß = 0.162, P = 0.002). After adjusting for confounding factors, per 1-standard deviation (SD) increase in the serum GDF15 levels was significantly related to an approximately 1.4-fold increased risk of LEAD in the total population (P < 0.05). Regardless of whether the BMI was < 25 kg/m2 or ≥ 25 kg/m2, this association remained significant, with approximately 1.6- and 1.4-fold increased risks of LEAD, respectively (both P < 0.05). CONCLUSIONS: High serum GDF15 levels were significantly correlated with an increased risk of LEAD in T2DM patients, and this relationship was independent of BMI.