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Various studies have revealed the association of metabolic diseases with inflammation. Mitochondria are key organelles involved in metabolic regulation and important drivers of inflammation. However, it is uncertain whether the inhibition of mitochondrial protein translation results in the development of metabolic diseases, such that the metabolic benefits related to the inhibition of mitochondrial activity remain unclear. Mitochondrial methionyl-tRNA formyltransferase (Mtfmt) functions in the early stages of mitochondrial translation. In this study, we reveal that feeding with a high-fat diet led to the upregulation of Mtfmt in the livers of mice and that a negative correlation existed between hepatic Mtfmt gene expression and fasting blood glucose levels. A knockout mouse model of Mtfmt was generated to explore its possible role in metabolic diseases and its underlying molecular mechanisms. Homozygous knockout mice experienced embryonic lethality, but heterozygous knockout mice showed a global reduction in Mtfmt expression and activity. Moreover, heterozygous mice showed increased glucose tolerance and reduced inflammation, which effects were induced by the high-fat diet. The cellular assays showed that Mtfmt deficiency reduced mitochondrial activity and the production of mitochondrial reactive oxygen species and blunted nuclear factor-κB activation, which, in turn, downregulated inflammation in macrophages. The results of this study indicate that targeting Mtfmt-mediated mitochondrial protein translation to regulate inflammation might provide a potential therapeutic strategy for metabolic diseases.

Obesity, and obesity-associated conditions such as hypertension, chronic kidney disease, type 2 diabetes, and cardiovascular disease, are important risk factors for severe Coronavirus disease-2019 (COVID-19). The common denominator is metaflammation, a portmanteau of metabolism and inflammation, which is characterized by chronically elevated levels of leptin and pro-inflammatory cytokines. These induce the "Suppressor Of Cytokine Signaling 1 and 3" (SOCS1/3), which deactivates the leptin receptor and also other SOCS1/3 sensitive cytokine receptors in immune cells, impairing the type I and III interferon early responses. By also upregulating SOCS1/3, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 adds a significant boost to this. The ensuing consequence is a delayed but over-reactive immune response, characterized by high-grade inflammation (e.g., cytokine storm), endothelial damage, and hypercoagulation, thus leading to severe COVID-19. Superimposing an acute disturbance, such as a SARS-CoV-2 infection, on metaflammation severely tests resilience. In the long run, metaflammation causes the "typical western" conditions associated with metabolic syndrome. Severe COVID-19 and other serious infectious diseases can be added to the list of its short-term consequences. Therefore, preventive measures should include not only vaccination and the well-established actions intended to avoid infection, but also dietary and lifestyle interventions aimed at improving body composition and preventing or reversing metaflammation.

Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation.

The current knowledge of sex-dependent differences in adipose tissue biology remains in its infancy and is motivated in part by the desire to understand why menopause is linked to an increased risk of metabolic disease. However, the development and characterization of targeted genetically-modified rodent models are shedding new light on the physiological actions of sex hormones in healthy reproductive metabolism. In this review we consider the need for differentially regulating metabolic flexibility, energy balance, and immunity in a sex-dependent manner. We discuss the recent advances in our understanding of physiological roles of systemic estrogen in regulating sex-dependent adipose tissue distribution, form and function; and in sex-dependent healthy immune function. We also review the decline in protective properties of estrogen signaling in pathophysiological settings such as obesity-related metaflammation and metabolic disease. It is clear that the many physiological actions of estrogen on energy balance, immunity, and immunometabolism together with its dynamic regulation in females make it an excellent candidate for regulating metabolic flexibility in the context of reproductive metabolism.

One of the concepts explaining the coincidence of obesity and type 2 diabetes (T2D) is the metaflammation theory. This chronic, low-grade inflammatory state originating from metabolic cells in response to excess nutrients, contributes to the development of T2D by increasing insulin resistance in peripheral tissues (mainly in the liver, muscles, and adipose tissue) and by targeting pancreatic islets and in this way impairing insulin secretion. Given the role of this not related to infection inflammation in the development of both: insulin resistance and insulitis, anti-inflammatory strategies could be helpful not only to control T2D symptoms but also to treat its causes. This review presents current concepts regarding the role of metaflammation in the development of T2D in obese individuals as well as data concerning possible application of different anti-inflammatory strategies (including lifestyle interventions, the extra-glycemic potential of classical antidiabetic compounds, nonsteroidal anti-inflammatory drugs, immunomodulatory therapies, and bariatric surgery) in the management of T2D.