Regulation of Adipocyte and Macrophage Functions by mTORC1 and 2 in Metabolic Diseases

Abstract

ScopeEvidence gathered in the last decades suggests that lipotoxicity and inflammation are the main factors connecting adipose tissue dysfunction to the development of metabolic diseases such as insulin resistance, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and certain types of cancer, among others. The mechanistic target of rapamycin (mTOR) is a serine threonine kinase that functions as the catalytic entity of two multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). These complexes are important components of signaling pathways activated by nutrients, growth factors, and inflammatory mediators and are therefore directly involved in the regulation of adipocyte and macrophage metabolism and function.Methods and ResultsIn this article, studies that evaluate the involvement of mTORC1 and 2 in the regulation of macrophage and adipocyte function and their implication in the development of metabolic‐disease‐associated adipose tissue dysfunction are reviewed.ConclusionIn adipocytes, optimal levels of mTORC1 activity are required for its pro‐lipogenic actions, while in macrophages, mTORC1 regulates features of both M1 and M2 polarization. mTORC2, on the other hand, promotes glucose uptake and de novo lipogenesis in adipocytes and counteracts macrophage inflammatory response.

Profiling of Matched Adipose and Skeletal Muscle in Human Pancreatic Cancer Cachexia Reveals Distinct Gene Profiles with Convergent Pathways

“…However, the exact mechanism through which the macrophages modulate adipose tissue mechanisms in cachexia remains to be elucidated [40]. In another interesting observation, mTOR and NF-kB signaling, which have long been implicated in muscle growth and wasting [41][42][43][44], were identified in adipose tissue here and are known to regulate lipogenesis and lipolysis respectively [45] [46,47]. Based on the IPA, mTOR signaling has a z-score of -2.4, indicating pathway inhibition.…”

Identification of MicroRNA-Target Gene-Transcription Factor Regulatory Networks in Colorectal Adenoma Using Microarray Expression Data

“…For example, the expression of target gene, KLF4, could be repressed by miR-34a, consequently suppressing anti-inflammatory phenotype macrophage polarization and exacerbating of obesity-related systemic inflammation and metabolic disorder (Pan et al, 2019). These miR-34a-regulated metabolic disorders such as obesity could induce mTORC1 activation (Festuccia, 2020), further contributing to downregulation of miR-29 expression (Slusarz and Pulakat, 2015). Members of the miR-29 family have garnered considerable attention due to their tumor-inhibition function as they were downregulated or silenced in a number of malignancies, such as colorectal cancer (Cristobal et al, 2015;Slusarz and Pulakat, 2015).…”

Role of mammalian target of rapamycin complex 2 in primary and secondary liver cancer

“…In addition, mTORC2 was involved in the progression of nonalcoholic fatty liver disease (NAFLD) by dysregulation of white adipose tissue. Thereby, de novo lipogenesis, lipolysis, glycolysis, and increased glucose uptake by GLUT4 are the mechanisms by which mTORC2 regulates adiposity and NAFLD[ 70 ]. Besides alcoholic and nonalcoholic liver disease, viral hepatitis is one of the main risk factors for the development of HCC.…”