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Graduate Student, University of California-San Diego

PINBOARD SUMMARY

Fatty acid biosynthesis and insulin response is reduced in adipocytes in inflammatory environment

Adipose tissue in obese individuals is characterized by inflammation, including high macrophage abundance and elevated TNF⍺ levels. This inflammatory microenvironment could have a major impact on the metabolic state of the adipocytes. Using 13C-metabolic flux analysis, we identified a major metabolic shift from primarily glucose and glutamine oxidation in pre-adipocytes to high catabolism of branched chain amino acids (BCAA) to support de novo lipogenesis (DNL) post-differentiation. We also sought to understand the impact of the proinflammatory cytokine, TNF⍺, on adipocyte metabolism. We developed a method using [U-13C6]glucose and gas chromatography-mass spectrometry to measure insulin-stimulated glucose metabolism that tracks the fate of glucose to pyruvate, lactate, and the tricarboxylic acid cycle. Overall, TNF⍺ increased glycolytic flux, decreased DNL, and reduced adipocyte insulin sensitivity. Metabolic reprogramming in response to inflammatory stress has broad implications and further study could yield a mechanistic understanding of metabolic disease pathology.

4 ITEMS PINNED

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.

Abstract: Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues. Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. However, the underlying molecular pathways are largely unknown. In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO). The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level. Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated. Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells. These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance. We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.

Pub.: 18 Dec '03, Pinned: 09 Jun '17

Obesity is associated with macrophage accumulation in adipose tissue.

Abstract: Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.

Pub.: 18 Dec '03, Pinned: 09 Jun '17