Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes

Abstract

Aims/hypothesis Metabolomics approaches in humans have identified around 40 plasma metabolites associated with insulin resistance (IR) and type 2 diabetes, which often coincide with those for obesity. We aimed to separate diabetesassociated from obesity-associated metabolite alterations in plasma and study the impact of metabolically important tissues on plasma metabolite concentrations. Methods Two obese mouse models were studied; one exclusively with obesity (ob/ob) and another with type 2 diabetes (db/db). Both models have impaired leptin signalling as a cause for obesity, but the different genetic backgrounds determine the susceptibility to diabetes. In these mice, we profiled plasma, liver, skeletal muscle and adipose tissue via semiquantitative GC-MS and quantitative liquid chromatography (LC)-MS/MS for a wide range of metabolites. Results Metabolite profiling identified 24 metabolites specifically associated with diabetes but not with obesity. Among these are known markers such as 1,5-anhydro-D-sorbitol, 3-hydroxybutyrate and the recently reported marker glyoxylate. New metabolites in the diabetic model were lysine, Ophosphotyrosine and branched-chain fatty acids. We also identified 33 metabolites that were similarly altered in both models, represented by branched-chain amino acids (BCAA) as well as glycine, serine, trans-4-hydroxyproline, and various lipid species and derivatives. Correlation analyses showed stronger associations for plasma amino acids with adipose tissue metabolites in db/db mice compared with ob/ob mice, suggesting a prominent contribution of adipose tissue to changes in plasma in a diabetic state. Conclusions/interpretation By studying mice with metabolite signatures that resemble obesity and diabetes in humans, we have found new metabolite entities for validation in appropriate human cohorts and revealed their possible tissue of origin.

NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis

“…3c). Our data is supported by previous reports of hepatic C18:2 accumulation in HF diet-induced NAFLD mice and ob/ob mice 8,21 . Next, we depleted FFAs from conditioned hepatocyte-culture medium.…”

Nat1 Deficiency Is Associated with Mitochondrial Dysfunction and Exercise Intolerance in Mice

“…Arginine and proline metabolism (L-aspartic acid, L-arginine, creatine, ornithine, L-proline, L-glutamic acid) pathways were the most significantly deregulated upon Nat1 depletion. Most of these metabolites have been associated with obesity and diabetes (Giesbertz et al, 2015). We also found a reduction in the quantity of glycine in Nat1 deficiency that is a well-established negative correlate to diabetes and obesity (Ferrannini et al, 2013; Giesbertz et al, 2015; Newgard et al, 2009; Wang-Sattler et al, 2012).…”

Concurrent profiling of polar metabolites and lipids in human plasma using HILIC-FTMS

“…To date, many of these studies focused on either the polar metabolite2021 or lipid fractions6222324. A comprehensive coverage of metabolites, however, is important when examining the biochemical activities in an organism because both polar metabolites and lipids in multiple metabolism pathways can often be simultaneously influenced by a single biological event, such as smoking25, inflammation26 and diabetes27. A few studies that refer to global plasma/serum metabolite profiling usually required dual extraction and/or dual separation2728293031, which are time consuming.…”

“…A comprehensive coverage of metabolites, however, is important when examining the biochemical activities in an organism because both polar metabolites and lipids in multiple metabolism pathways can often be simultaneously influenced by a single biological event, such as smoking25, inflammation26 and diabetes27. A few studies that refer to global plasma/serum metabolite profiling usually required dual extraction and/or dual separation2728293031, which are time consuming. Therefore, it’s necessary to develop a single extraction-single separation approach for concurrent analysis of both polar metabolites and lipids in blood plasma.…”