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  • The importance of insulin in controlling lipolysis and fat m

    2024-06-11

    The importance of insulin in controlling lipolysis and fat mass is further emphasized by mouse models with alterations in the insulin signaling pathway of adipocytes. For example, mice with a tamoxifen-inducible knockout of the insulin receptor in mature adipocytes reveal a substantial decrease of adipose tissue mass due to increased lipolysis and adipocyte apoptosis resembling most of the features of the Arfrp1 phenotype [39]. Furthermore, the sorting receptor SORLA was recently identified to interact with the insulin receptor in adipocytes facilitating its redirection to the cell surface and enhancing insulin signal reception. Accordingly, mice overexpressing SORLA specifically in adipocytes revealed higher insulin receptor surface levels and decreased lipolysis, which promotes the acquisition of fat tissue and exacerbates diet-induced obesity, while SORLA knockout mice showed excessive lipolysis and a reduction in WAT mass [40]. Notably, numerous genetic variants encoding proteins involved in vesicular transportation (e.g. ARL15, Hip1, Rab3gap1) have been identified by genome-wide association studies (GWAS) as being associated with type 2 diabetes-related traits in humans [41]. These findings further highlight the relevance of functional intracellular vesicle trafficking in preserving metabolic health.
    Conclusions
    Funding This work was supported by the German Ministry of Education and Research and the Brandenburg State (BMBF; DZD grant 82DZD00302) and by the German Research Foundation (DFG; SFB 958).
    Acknowledgements
    Introduction The increasing prevalence of aging-related disorders, including neurodegeneration, cardiovascular disease (CVD), sarcopenia, osteoporosis, and immunological disorders, is associated with expansion of the older population worldwide [1]. Given that metabolic disorders, such as type 2 how to find molarity of solution (T2DM), are linked to these diseases, anti-insulin resistance has become a paradigm of therapy [1]. This is particularly important for aging-associated neurodegenerative diseases, including AD and Parkinson’s disease (PD), for which no therapies are available [2]. Insulin, glucagon like peptide-1 receptor agonists, and inhibitors of dipeptidyl peptidase 4 have been studied 3, 4, 5 with promising results in small-scale trials 3, 4, but the results require validation in larger clinical studies. APN is a multifunctional adipocytokine that is also referred to as GBP-28, apM1, AdipoQ, and Acrp30 [6]. It is produced predominantly in adipose tissues, in which it is synthesized as a 28-kDa monomer, followed by post-translational modifications, such as glycosylation and oligomerization, to different molecular weight multimers 6, 7, 8. APN is involved in diverse biological processes, including sensitization of the insulin receptor signaling pathway, suppression of inflammation, and stimulation of mitochondria biogenesis [6]. At the cellular level, the effects of APN are mediated through activation of transmembrane receptors, AdipoR1 and -R2, and their downstream signaling pathways. In the nervous system, this signaling is mediated by molecules such as AMP-activated protein kinase and peroxisome proliferator-activated receptor γ, which have essential roles in insulin sensitivity and oxidative metabolism, whereas other kinases, such as p38 MAP kinase and GSK-3β, are involved in neurogenesis and suppression of neurodegeneration 6, 8. It is well characterized that APN is beneficial for metabolic syndrome and related diseases. Similarly, it is generally believed that APN might be protective in other types of disease, including cardiovascular and neurodegenerative diseases [9]. However, accumulating evidence suggests that APN is not simply a protective molecule. Indeed, APN might exacerbate various chronic diseases in advanced stages, including CHF and CKD 8, 10. Furthermore, a recent prospective cohort study showed that hyperadiponectinemia was correlated with cognitive deficits and amyloid deposits in older patients, suggesting that APN is a risk factor for AD [11]. In this context, here we discuss the role of altered serum APN levels in some chronic diseases and propose a novel therapy strategy using antagonists of APR receptors for such disorders, which is distinct from the current strategy using APN agonists for the therapy of metabolic syndrome.