Lactate Is a Key Mediator That Links Obesity to Insulin Resistance via Modulating Cytokine Production From Adipose Tissue

Abstract

Numerous evidences indicate that inflammation in adipose tissue is the primary cause of systemic insulin resistance induced by obesity. Obesity-associated changes in circulating LPS level and hypoxia/HIF-1α activation have been proposed to be involved in boosting obesity-induced inflammation. However, what triggers obesity-induced inflammation is poorly understood. In this study, we pinpoint lactate as a key trigger to mediate obesity-induced inflammation and systemic insulin resistance. Specific deletion of Slc16a1 that encodes MCT1, the primary lactate transporter in adipose tissues, robustly elevates blood levels of pro-inflammatory cytokines and aggravates systemic insulin resistance without alteration of adiposity in mice fed high-fat diet. Slc16a1 deletion in adipocytes elevates intracellular lactate level while reducing circulating lactate concentration. Mechanistically, lactate retention due to Slc16a1 deletion initiates adipocyte apoptosis and cytokine release. The locally recruited macrophages amplify the inflammation by release of pro-inflammatory cytokines to the circulation, leading to insulin resistance in peripheral tissues. This study, therefore, indicates that lactate within adipocytes has a key biological function linking obesity to insulin resistance, and harnessing lactate in adipocytes can be a promising strategy to break this deadly link.

Monocarboxylate transporter 1 deficiency impacts CD8+ T lymphocytes proliferation and recruitment to adipose tissue during obesity

“…In conclusion, our findings highlight a distinct effect of MCT1 deficiency in CD8 + T cells on adipocytes, supporting the concept that reprogramming of lymphocytes could impact the immune-adipose tissue axis in the context of obesity without a major impact of systemic metabolism. Indeed, as showed by Lin et al. (2022) , the specific deletion of Slc16a1 in adipose tissue can elicit a vicious cycle of inflammatory response via the functional interaction between adipocytes and macrophages and likely other immune cells, e.g., in our case in which CD8 + T cells were involved.…”

Lysine acetylation of Escherichia coli lactate dehydrogenase regulates enzyme activity and lactate synthesis

“…This approach enables rational design of lysine acetylated sites and promotes the potential applications of lysine acetylation in microbial synthesis. Furthermore, as lactate has been proved to play an important role in pathogenesis of cancer and diabetes (Feng et al, 2018;Lin et al, 2022), our results may provide some important references for the treatment of these diseases.…”

“…NAD-dependent lactate dehydrogenase (LdhA) is a conserved protein presented in many species, specific for lactate biosynthesis from pyruvate. In human, lactate has been proved to play an important role in pathogenesis of cancer and diabetes ( Feng et al, 2018 ; Lin et al, 2022 ), and lysine acetylation regulates the activity of human LdhA, further affecting cell migration and proliferation in pancreatic cancer ( Zhao et al, 2013 ). On the other hand, lactate itself is an important bulk chemical, widely used in the fields of cosmetics, herbicides and pharmaceutical ( Feng et al, 2014 ; Choi et al, 2019 ).…”

Mutual regulation of lactate dehydrogenase and redox robustness

“…Further reports suggest that lactate leads to regulation of post-GAPDH glycolytic intermediates and T cell proliferation via the NAD(H) redox state (Quinn et al, 2020). In efficient glycolytic organs like adipose tissues, alteration of lactate transport promotes apoptosis of adipocytes, resulting in severe insulin resistance (Lin et al, 2022). All the research studies show that the redox homeostasis maintained by lactate decides cell fate.…”

“…The expression and phosphorylation of LDHA might be involved in type 1 diabetes by β-cell apoptosis (Huang et al, 2021). Lactate production is highly increased during obesity (Lin et al, 2022), while hypothalamic LDHA is regulated by leptin signaling in obese rats (Abraham et al, 2018). Due to these effects, some researchers tried mediating LDH to intervene in metabolic syndromes.…”