HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO3 fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO3-injected mice lacking Saa1.1 and Saa2.1 exhibited a partial restoration of antiinflammatory and cholesterol efflux properties in adipocytes. Conversely, incorporation of SAA into HDL preparations reduced antiinflammatory properties but not to the same extent as HDL from AgNO3-injected mice. SAA-enriched HDL colocalized with cell surface–associated extracellular matrix (ECM) of adipocytes, suggesting impaired access to the plasma membrane. Enzymatic digestion of proteoglycans in the ECM restored the ability of SAA-containing HDL to inhibit palmitate-induced inflammation and cholesterol efflux. Collectively, these findings indicate that inflammation results in a loss of the antiinflammatory properties of HDL on adipocytes, which appears to partially result from the SAA component of HDL binding to cell-surface proteoglycans, thereby preventing access of HDL to the plasma membrane.
It is well recognized that adipose tissue in obesity is characterized by macrophage accumulation and local inflammation. This review summarizes current evidence regarding dietary cholesterol on adipose tissue macrophage accrual, systemic inflammation and its potential link to atherosclerosis.Based upon epidemiological data and animal studies, both obesity and dietary cholesterol have been associated with coronary artery disease. However, the effect of dietary cholesterol on adipose tissue has not been widely studied. In an animal model of obesity/metabolic syndrome, feeding a diabetogenic diet high in saturated fat and refined carbohydrate with 0.15% cholesterol added resulted in increased adipose tissue macrophage accumulation, local inflammation and chronic systemic inflammation compared to animals that received the same diet without added cholesterol. There also was an increased macrophage content of atherosclerotic lesions observed in the added cholesterol group.Mechanisms involved in adipose tissue macrophage accrual continue to be elusive. There are limited data that dietary cholesterol may worsen macrophage accumulation in adipose tissue and the artery wall. Cytokines produced by inflamed adipose tissue may lead to inflammatory changes in the liver, which could then play a role in atherogenesis.
Insulin resistance in obesity is believed to be propagated by adipose tissue and liver inflammation. HMGB1 is a multifunctional protein that is pro-inflammatory when released from cells. It has been previously demonstrated that anti-HMGB1 antibody reduces atherosclerotic lesion pro-inflammatory cells and progression of atherosclerosis in a mouse model. To test the potential beneficial role of blocking HMGB1 in adipose tissue and liver inflammation in mice fed an obesogenic diet, we administered anti-HMGB1 antibody to C57Bl/6 mice fed a high (60%)-fat diet. The mice were treated with weekly injections of an anti-HMGB1 antibody or anti-KLH antibody (isotype control) for 16 weeks. Mice that received the anti-HMGB1 antibody gained less weight than the control-treated animals. Anti-HMGB1 treatment also reduced hepatic expression of TNF-alpha and MCP-1, molecules that promote inflammation. However, adipose tissue inflammation, as measured by gene expression analyses and immunohistochemistry, did not differ between the two groups. There also were no differences in glucose or insulin tolerance between the two groups. When feeding mice a high-fat diet, these data suggest that HMGB1 may have a crucial role in weight gain and liver inflammation.
Management of individuals with type 2 diabetes involves complex decision-making to attain good glycemic control. A personalized approach to the care of these individuals provides a unique management plan for each patient. This article reviews some of the important variables that require consideration for management of individuals with type 2 diabetes. We also provide a scoring scale to help clinicians make appropriate decisions regarding A1C targets while caring for these patients.
Hypertriglyceridemia (HTG) can result from a variety of causes. Mild to moderate HTG occurs commonly as part of the metabolic syndrome, can be the result of multiple genetic mutations in an individual or family, and can be secondary to several diseases and drugs. Severe HTG with plasma triglyceride (TG) levels >1000-1500 mg/dL can result from 3 groups of conditions: (1) rare mutations in the lipoprotein lipase (LPL) complex, where it is termed the familial chylomicronemia syndrome (FCS), (2) the co-existence of genetic and secondary forms of HTG, termed the multifactorial chylomicronemia syndrome (MFCS), which is a much more common cause of severe HTG, and (3) familial partial lipodystrophy (FPLD). Mild to moderate HTG is associated with an increased risk of premature cardiovascular disease (CVD), while severe HTG can lead to pancreatitis and other features of the chylomicronemia syndrome, as well as an increased risk of premature CVD. Appropriate management of the patient with HTG requires knowledge of the likely cause of the HTG, in order to prevent its complications. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG .
Obesity is characterized by adipocyte hypertrophy and macrophage accumulation in adipose tissue. Monocyte chemoattractant protein-1 (MCP-1) plays a role in macrophage recruitment into adipose tissue. However, other adipocyte-derived factors, e.g., hyaluronan and serum amyloid A (SAA), can facilitate monocyte adhesion and chemotaxis, respectively. The objective was to test the potential involvement of these factors in macrophage recruitment. Differentiated 3T3-L1 adipocytes made hypertrophic by growth in high glucose conditions were used to study SAA and hyaluronan regulation in vitro. Two mouse models of obesity were used to study their expression in vivo. Nuclear factor-kappaB was upregulated and peroxisome proliferator-activated receptor (PPAR)gamma was downregulated in hypertrophic 3T3-L1 cells, with increased expression of SAA3 and increased hyaluronan production. Rosiglitazone, a PPARgamma agonist, reversed these changes. Hypertrophic adipocytes demonstrated overexpression of SAA3 and hyaluronan synthase 2 in vitro and in vivo in diet-induced and genetic obesity. SAA and hyaluronan existed as part of a complex matrix that increased the adhesion and retention of monocytes. This complex, purified by binding to a biotinylated hyaluronan binding protein affinity column, also showed monocyte chemotactic activity, which was dependent on the presence of SAA3 and hyaluronan but independent of MCP-1. We hypothesize that adipocyte hypertrophy leads to increased production of SAA and hyaluronan, which act in concert to recruit and retain monocytes, thereby leading to local inflammation in adipose tissue.
Numerous studies have demonstrated the clinical benefits of continuous glucose monitoring (CGM) use in individuals with type 1 diabetes and type 2 diabetes (T2D) who are treated with intensive insulin therapy. A growing body of evidence suggests that CGM use may also confer similar glycemic benefits in T2D individuals who are treated with less-intensive therapies. Investigators are also exploring the potential use of CGM as an aid in weight management. This article reviews the continuing evolution of CGM, focusing on how CGM may be used to improve glycemic control and promote adoption of desired health behaviors within broader T2D and prediabetes populations.
