Obesity and Metabolomics: Metallothioneins Protect Against High-Fat Diet-Induced Consequences in Metallothionein Knockout Mice

Abstract

Obesity continues to rise as an alarming global epidemic. System level mechanisms, diagnostics, and therapeutics are sorely needed so as to identify at risk individuals and design appropriate population scale interventions. The present study evaluated the protective role of metallothioneins (MTs) against obesity and high-fat diet-induced effects such as insulin resistance in both male and female MT-1+2 knockout and MT-3 knockout mice. As the metabolome is closest to the functional phenotype, changes in metabolite levels were also evaluated, and the direct or indirect involvement of MTs in metabolism examined. MT-1+2-, MT-3 knockout, and wild-type mice were given a high-fat diet for 2 months. Variation in body weight gain, tissue weight, and response to oral glucose tolerance test and insulin tolerance test were determined and compared to mice that received the control diet. Effect of the high-fat diet on the knockout mice were investigated on the metabolome level in specific tissues using metabolomics. Both knockout mice strains were more susceptible to high-fat diet-induced effects, such as weight gain and moderate insulin resistance, with the MT-3 knockout mice most susceptible. Brain tissue of the knockout mice showed most metabolic variation and pointed to possible impairment of mitochondrial function. The protective effect of MTs against high-fat diet and obesity-induced effects such as insulin resistance was evident from our observations. The putative role MTs play in mitochondrial function is possibly the main contributor to the lack of these effects in wild-type mice. Considering the expression profiles of the MT isoforms and similarity in brain metabolic variation in the knockout strains, it appears that they promote mitochondrial function in the hypothalamus, thereby limiting weight gain and insulin resistance. Furthermore, metabolomics research in preclinical models of obesity and in the clinic is warranted in the near future.

Metabolic Biomarkers and Neurodegeneration: A Pathway Enrichment Analysis of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

“…Metabolomics has found recent broad applications in both preclinical and clinical research (Embade et al, 2016;Kim et al, 2011;Lindeque et al, 2015;Lopes et al, 2015). The metabolome, one of the end products of gene-environment interactions immediately upstream to their phenotypic impacts, can help characterize and discriminate pathophysiological signatures of AD (Sapkota et al, 2015), PD (Hatano et al, 2016), and ALS (Blasco et al, 2016).…”

Metallothioneins regulate the adipogenic differentiation of 3T3-L1 cells via the insulin signaling pathway

“…showed that MT3 KO mice significantly increased their body weight through the intake of a HFD compared with wild type mice. [17] Male hybrid MTKO mice (129/Ola and C57BL/6J background) and MT3 KO (C67/BL6 and 129/Sv background) exhibited obesity. [18,19] Interestingly, these KO mice already had a higher body weight than the wild type (WT) mice at age 3–4 months old, i.e., prior to HFD feeding.…”

“…[18,19] Interestingly, these KO mice already had a higher body weight than the wild type (WT) mice at age 3–4 months old, i.e., prior to HFD feeding. [17] Therefore, MTs may be involved in the regulation of the number of adipocytes and WAT formation at earlier stages, which would contribute to later obesity induced by HFD feeding.…”

“Omics” Prospective Monitoring of Bariatric Surgery: Roux-En-Y Gastric Bypass Outcomes Using Mixed-Meal Tolerance Test and Time-Resolved1H NMR-Based Metabolomics

“…Lifestyle, diet, and pharmacotherapies account for less than 10% excess weight loss (Khan et al, 2015). However, bariatric surgery is indicated only for patients with morbid obesity (body mass index [BMI] >40 kg/m 2 ) or in cases of moderate obesity associated with comorbidities, particularly the type 2 diabetes (Bruce and Mitchell, 2015;Lindeque et al, 2015).…”