Adiponectin is an adipokine that exerts insulin-sensitizing and anti-inflammatory roles in insulin target tissues including liver. While the insulin-sensitizing function of adiponectin has been extensively investigated, the precise mechanism by which adiponectin alleviates diet-induced hepatic inflammation remains elusive. Here, we report that hepatocyte-specific knockout (KO) of the adaptor protein APPL2 enhanced adiponectin sensitivity and prevented mice from developing high-fat diet-induced inflammation, insulin resistance, and glucose intolerance, although it caused fatty liver. The improved anti-inflammatory and insulin-sensitizing effects in the APPL2 hepatocyte-specific KO mice were largely reversed by knocking out adiponectin. Mechanistically, hepatocyte APPL2 deficiency enhances adiponectin signaling in the liver, which blocks TNF-a-stimulated MCP-1 expression via inhibiting the mTORC1 signaling pathway, leading to reduced macrophage infiltration and thus reduced inflammation in the liver. With results taken together, our study uncovers a mechanism underlying the anti-inflammatory role of adiponectin in the liver and reveals the hepatic APPL2-mTORC1-MCP-1 axis as a potential target for treating overnutrition-induced inflammation in the liver.Obesity is a major medical problem worldwide. It is associated with insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). It is currently believed that overnutrition-induced chronic inflammation is one of the key mechanisms underlying obesity-induced metabolic diseases (1,2).Adiponectin is an adipose tissue-derived hormone that possesses antidiabetes and anti-inflammatory functions (3). Circulating levels of adiponectin are inversely associated with obesity and type 2 diabetes. Administration of adiponectin into diabetic mouse models restores insulin sensitivity by improving glucose metabolism (4). Adiponectin has also been shown to exert an anti-inflammatory role by suppressing inflammatory responses in macrophages, adipocytes, and endothelial cells (5). A number of studies reveal an inverse correlation of circulating adiponectin levels with liver inflammation (6) and NAFLD (7); however, the molecular mechanism underlying the antiinflammatory action of adiponectin, especially in hepatocytes, remains largely unknown.Adiponectin exerts its beneficial effects via binding to its plasma membrane receptors, including AdipoR1, AdipoR2,8). While AdipoR1 is ubiquitously expressed in most tissues, AdipoR2 is primarily expressed in the liver (9) and T-cadherin is absent in hepatocytes under physiological conditions (10). APPL1 and APPL2 are two scaffold proteins that bind directly to AdipoR1/R2. The binding of APPL1 with AdipoR1 and AdipoR2 positively mediates adiponectin signaling (11) and facilitates the cross talk between adiponectin and insulin signal pathways (12). APPL2, an APPL1 isoform displaying 54% identity in

Adiponectin is an adipokine with anti-insulin resistance and anti-inflammatory functions. It exists in serum predominantly in three multimeric complexes: the trimer, hexamer, and high-molecular-weight forms. Although recent studies indicate that adiponectin promotes wound healing in rodents, its role in the wound healing process in humans is unknown. This study investigated the expression levels of adiponectin in adipose tissue and serum of women who experienced either normal or delayed wound healing after abdominal plastic surgery. We found that obese women with delayed healing had slightly lower total adiponectin levels in their adipose tissue compared with women with normal healing rates. Among the different isoforms of adiponectin, levels of the trimer forms were significantly reduced in adipose tissue, but not the serum, of obese women with delayed healing compared to women who healed normally. This study provides clinical evidence for a potential role of low-molecular-weight oligomers of adiponectin in the wound healing process as well as implications for an autocrine and/or paracrine mechanism of adiponectin action in adipose tissues.

Mutations in the scaffolding domain of Receptor Interacting Protein kinases (RIP) underlie the recently described human autoimmune syndrome, CRIA, characterized by lymphadenopathy, splenomegaly, and autoantibody production. While disease mechanisms for CRIA remain undescribed, RIP kinases work together with caspase-8 to regulate cell death, which is critical for normal differentiation of many cell types. Here, we describe a key role for RIP1 in facilitating innate B cell differentiation and subsequent activation. By comparing RIP1, RIP3, and caspase-8 triple deficient and RIP3, caspase-8 double deficient mice, we identified selective contributions of RIP1 to an accumulation of murine splenic Marginal Zone (MZ) B cells and B1-b cells. We used mixed bone-marrow chimeras to determine that innate B cell commitment required B cell-intrinsic RIP1, RIP3, and caspase-8 sufficiency. RIP1 regulated MZ B cell development rather than differentiation and RIP1 mediates its innate immune effects independent of the RIP1 kinase domain. NP-KLH/alum and NP-Ficoll vaccination of mice doubly deficient in both caspase-8 and RIP3 or deficient in all three proteins (RIP3, caspase-8, and RIP1) revealed uniquely delayed T-dependent and T-independent IgG responses, abnormal splenic germinal center architecture, and reduced extrafollicular plasmablast formation compared to WT mice. Thus, RIP kinases and caspase-8 jointly orchestrate B cell fate and delayed effector function through a B cell-intrinsic mechanism.

Adiponectin is an adipokine that exerts insulin sensitizing and anti-inflammatory roles in insulin target tissues including liver. While the insulin sensitizing function of adiponectin has been extensively investigated, the precise mechanism by which adiponectin alleviates diet-induced hepatic inflammation remains elusive. Here, we report that hepatocyte-specific knockout of the adaptor protein APPL2 enhanced adiponectin sensitivity and prevented mice from high fat diet-induced inflammation, insulin resistance, and glucose intolerance, although it caused fatty liver. The improved anti-inflammatory and insulin sensitizing effects in the APPL2 hepatocyte-specific knockout mice were largely reversed by knocking out adiponectin. Mechanistically, hepatocyte APPL2 deficiency enhances adiponectin signaling in the liver, which blocks TNF-a-stimulated MCP-1 expression via inhibiting the mTORC1 signaling pathway, leading to reduced macrophage infiltration and thus reduced inflammation in the liver. Taken together, our study uncovers a mechanism underlying the anti-inflammatory role of adiponectin in the liver and reveals the hepatic APPL2-mTORC1-MCP-1 axis as a potential target for treating overnutrition-induced inflammation in the liver.

No abstract