No abstract

The current dogma is that obesity-associated hepatic inflammation is due to increased Kupffer cell (KC) activation. However, recruited hepatic macrophages (RHMs) were recently shown to represent a sizable liver macrophage population in the context of obesity. Therefore, we assessed whether KCs and RHMs, or both, represent the major liver inflammatory cell type in obesity. We used a combination of in vivo macrophage tracking methodologies and adoptive transfer techniques in which KCs and RHMs are differentially labeled with fluorescent markers. With these approaches, the inflammatory phenotype of these distinct macrophage populations was determined under lean and obese conditions. In vivo macrophage tracking revealed an approximately sixfold higher number of RHMs in obese mice than in lean mice, whereas the number of KCs was comparable. In addition, RHMs comprised smaller size and immature, monocyte-derived cells compared with KCs. Furthermore, RHMs from obese mice were more inflamed and expressed higher levels of tumor necrosis factor-α and interleukin-6 than RHMs from lean mice. A comparison of the MCP-1/C-C chemokine receptor type 2 (CCR2) chemokine system between the two cell types showed that the ligand (MCP-1) is more highly expressed in KCs than in RHMs, whereas CCR2 expression is approximately fivefold greater in RHMs. We conclude that KCs can participate in obesity-induced inflammation by causing the recruitment of RHMs, which are distinct from KCs and are not precursors to KCs. These RHMs then enhance the severity of obesity-induced inflammation and hepatic insulin resistance.

Background: NAT8L (N-acetyltransferase 8-like) synthesizes N-acetylaspartate and is required for myelination in the brain. Its function in other tissues was undefined. Results: Nat8l is highly expressed in adipose tissues and impacts adipogenic marker gene expression, lipid turnover, and energy metabolism in brown adipocytes. Conclusion: Nat8l expression influences cellular bioenergetics in adipocytes. Significance: These findings establish a novel pathway in brown adipocyte metabolism.

No abstract

We have developed a method for reconstructing gene association networks and have applied this method to gene profiles from 3T3-L1 cells. Priorization of the candidate genes pinpointed a transcript annotated as APMAP (adipocyte plasma membrane-associated protein). Functional studies showed that APMAP is upregulated in murine and human adipogenic cell models as well as in a genetic mouse model of obesity. Silencing APMAP in 3T3-L1 cells strongly impaired the differentiation into adipocytes. Moreover, APMAP expression was strongly induced by the PPARγ ligand rosiglitazone in adipocytes in vitro and in vivo in adipose tissue. Using ChIP-qPCR and luciferase reporter assays, we show a functional PPARγ binding site. In addition, we provide evidence that the extracellular C-terminal domain of APMAP is required for the function of APMAP in adipocyte differentiation. Finally, we demonstrate that APMAP translocates from the endoplasmatic reticulum to the plasma membrane during adipocyte differentiation.

Highlights d GPR120 is a PPARg target gene in adipocytes d GPR120 activation blocks the inhibitory phosphorylation of PPARg at S273 d GPR120 activation increases the endogenous PPARg ligand 15d-PGJ2 in adipose tissue d Combined PPARg and GPR120 agonism potentiates insulin sensitivity in diabetic mice

The beneficial roles of omega-3 fatty acids (ω3-FAs) on obesity, type 2 diabetes, and other metabolic diseases are well known. Most of these effects can be explained by their anti-inflammatory effects triggered through their receptor, free fatty acid receptor 4 (FFAR4) activation. Although the whole mechanism of action is not fully described yet, it has been shown that stimulation of ω3-FA to FFAR4 is followed by receptor phosphorylation. This makes FFAR4 to be capable of interacting with β-arrestin-2, which in turn, results in association of β-arrestin-2 with TAB1. This stealing of an important partaker of the inflammatory cascade leads to interruption of the pathway, resulting in reduced inflammation. Besides this regulation of the anti-inflammatory response, FFAR4 signaling also has been shown to regulate glucose homeostasis, adiposity, gastrointestinal peptide secretion, and taste preference. In this review, we summarize the current knowledge about the interaction of ω3-FAs with FFAR4 and the consequent opportunities for the application of ω3-FAs and possible FFAR4 targets.

Elevated circulating fatty acids (FAs) contribute to obesity-associated metabolic complications, but the mechanisms by which insulin suppresses lipolysis are poorly understood. We show that α/β-hydrolase domain-containing 15 (ABHD15) is required for the anti-lipolytic action of insulin in white adipose tissue (WAT). Neither insulin nor glucose treatments can suppress FA mobilization in global and conditional Abhd15-knockout (KO) mice. Accordingly, insulin signaling is impaired in Abhd15-KO adipocytes, as indicated by reduced AKT phosphorylation, glucose uptake, and de novo lipogenesis. In vitro data reveal that ABHD15 associates with and stabilizes phosphodiesterase 3B (PDE3B). Accordingly, PDE3B expression is decreased in the WAT of Abhd15-KO mice, mechanistically explaining increased protein kinase A (PKA) activity, hormone-sensitive lipase (HSL) phosphorylation, and undiminished FA release upon insulin signaling. Ultimately, Abhd15-KO mice develop insulin resistance. Notably, ABHD15 expression is decreased in humans with obesity and diabetes compared to humans with obesity and normal glucose tolerance, identifying ABHD15 as a potential therapeutic target to mitigate insulin resistance.