Impaired white adipose tissue fatty acid metabolism in mice fed a high-fat diet worsened by arsenic exposure, primarily affecting retroperitoneal adipose tissue.

Fatty acid (FA) metabolism dysfunction of white adipose tissue (WAT) underlies obesity and insulin resistance in response to high calorie intake and/or endocrine-disrupting chemicals (EDCs), among other factors. Arsenic is an EDC that has been associated with metabolic syndrome and diabetes. However, the combined effect of a high-fat diet (HFD) and arsenic exposure on WAT FA metabolism has been little studied. FA metabolism was evaluated in visceral (epididymal and retroperitoneal) and subcutaneous WAT of C57BL/6 male mice fed control or HFD (12 and 40% kcal fat, respectively) for 16 weeks together with an environmentally relevant chronic arsenic exposure through drinking water (100 µg/L) during the second half of the study. In mice fed HFD, arsenic potentiated the increase of serum markers of selective insulin resistance in WAT and fatty acid re-esterification and the decrease of the lipolysis index. Retroperitoneal was the WAT most affected, where the combination of arsenic and HFD in contrast to HFD, generated higher adipose weight, larger adipocytes, increased triglyceride content, and decreased fasting stimulated lipolysis evidenced by lower phosphorylation of HSL and perilipin. At the transcriptional level, arsenic in mice fed either diet downregulated genes involved in fatty acid uptake (LPL, CD36), oxidation (PPARα, CPT1), lipolysis (ADRß3) and glycerol transport (AQP7 and AQP9). Additionally, arsenic potentiated hyperinsulinemia induced by HFD, despite a slight increase in weight gain and food efficiency. Thus, the second hit of arsenic in sensitized mice by HFD worsens fatty acid metabolism impairment in WAT, mainly retroperitoneal, along with an exacerbated insulin resistance phenotype.

Is insulin resistance tissue-dependent and substrate-specific? The role of white adipose tissue and skeletal muscle.

Insulin resistance (IR) refers to a reduction in the ability of insulin to exert its metabolic effects in organs such as adipose tissue (AT) and skeletal muscle (SM), leading to chronic diseases such as type 2 diabetes, hepatic steatosis, and cardiovascular diseases. Obesity is the main cause of IR, however not all subjects with obesity develop clinical insulin resistance, and not all clinically insulin-resistant people have obesity. Recent evidence implies that IR onset is tissue-dependent (AT or SM) and/or substrate-specific (glucometabolic or lipometabolic). Therefore, the aims of the present review are 1) to describe the glucometabolic and lipometabolic activities of insulin in AT and SM in the maintenance of whole-body metabolic homeostasis, 2) to discuss the pathophysiology of substrate-specific IR in AT and SM, and 3) to highlight novel validated tests to assess tissue and substrate-specific IR that are easy to perform in clinical practice. In AT, glucometabolic IR reduces glucose availability for glycerol and fatty acid synthesis, thus decreasing the esterification and synthesis of signaling bioactive lipids. Lipometabolic IR in AT impairs the antilipolytic effect of insulin and lipogenesis, leading to an increase in circulating FFAs and generating lipotoxicity in peripheral tissues. In SM, glucometabolic IR reduces glucose uptake, whereas lipometabolic IR impairs mitochondrial lipid oxidation, increasing oxidative stress and inflammation, all of which lead to metabolic inflexibility. Understanding tissue-dependent and substrate-specific IR is of paramount importance for early detection before clinical manifestations and for the development of more specific treatments or direct interventions to prevent chronic life-threatening diseases.

Leptin and adiponectin synthesis and secretion in mature 3T3-L1 adipocytes are differentially down-regulated by arsenic and palmitic acid exposure throughout different stages of adipogenesis.

AIMS: Arsenic is a risk factor for type 2 diabetes and cardiovascular disease. However, little is known about arsenic effects over adipocyte endocrine functionality, particularly for leptin and adiponectin, and about its interaction with dietary components, which are the main environmental regulators of adipose tissue functionality. The aim of this work was to evaluate leptin and adiponectin in mature 3T3-L1 adipocytes exposed to palmitate (simulating excess fat intake), arsenite, or both throughout two different stages of adipogenesis. MATERIAL AND METHODS: 3T3-L1 adipocytes were exposed starting from the beginning of its differentiation process during 11 d or once adipocytes were mature for 72 h. Adipokines secretion was evaluated by ELISA, intracellular protein levels and secreted adiponectin multimers by Western blot and mRNA abundance by qPCR. KEY FINDINGS: Leptin and adiponectin secretion decreased by arsenite alone or in combination with palmitate due to reduced gene and protein expression of both adipokines. However, leptin was impaired more at the transcriptional level, whereas affections to adiponectin were more relevant at the intracellular protein amount level with changes in the multimers proportion. The gene expression of several of their transcription factors was altered. Additionally, the magnitude of the effects depends on the adipocyte cell stage at which exposure began; adiponectin was more affected when exposure started from differentiation and leptin once adipocytes were mature. SIGNIFICANCE: These results in an in vivo model could be translated into less satiety and reduced insulin sensitivity.