Weight cycling increases T-cell accumulation in adipose tissue and impairs systemic glucose tolerance.

Obesity is one of the leading causes of morbidity in the U.S. Accumulation of proinflammatory immune cells in adipose tissue (AT) contributes to the development of obesity-associated disorders. Weight loss is the ideal method to counteract the negative consequences of obesity; however, losses are rarely maintained, leading to bouts of weight cycling. Fluctuations in weight have been associated with worsened metabolic and cardiovascular outcomes; yet, the mechanisms explaining this potential correlation are not known. For determination of whether weight cycling modulates AT immune cell populations, inflammation, and insulin resistance, mice were subjected to a diet-switch protocol designed to induce weight cycling. Weight-cycled mice displayed decreased systemic glucose tolerance and impaired AT insulin sensitivity when compared with mice that gained weight but did not cycle. AT macrophage number and polarization were not modulated by weight cycling. However, weight cycling did increase the number of CD4(+) and CD8(+) T cells in AT. Expression of multiple T helper 1-associated cytokines was also elevated subsequent to weight cycling. Additionally, CD8(+) effector memory T cells were present in AT of both obese and weight-cycled mice. These studies indicate that an exaggerated adaptive immune response in AT may contribute to metabolic dysfunction during weight cycling.

Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis.

OBJECTIVE: Elevated serum free fatty acid levels are associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. Macrophages are recruited to atherosclerotic plaques and metabolic tissues during obesity and accumulate lipids, including free fatty acids. We investigated the molecular consequences of intracellular saturated free fatty acid accumulation in macrophages. METHODS AND RESULTS: Previously, we demonstrated that cotreatment of mouse peritoneal macrophages (MPMs) with stearic acid and triacsin C (an inhibitor of long-chain acyl coenzyme A synthetases) results in intracellular free fatty acid accumulation and apoptosis. Here, we used Western blotting analysis, real-time reverse transcription polymerase chain reaction, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining to assess endoplasmic reticulum (ER) stress, inflammation, and apoptosis in MPMs. Intracellular stearic acid accumulation induces Toll-like receptor 4/2-independent inflammation that results in ER stress-mediated apoptosis of MPMs. Polarization of MPMs to a proinflammatory M1 phenotype increases their susceptibility to inflammation and ER stress, but not apoptosis, in response to cotreatment with stearic acid and triacsin C. CONCLUSIONS: Intracellular accumulation of stearic acid in MPMs activates inflammatory signaling, leading to ER stress-mediated apoptosis. M1 macrophages are more prone to stearic acid-induced inflammation and ER stress. These same pathways may be activated in macrophages residing in atherosclerotic plaques and metabolic tissues during conditions of obesity and hyperlipidemia.

Aberrant accumulation of undifferentiated myeloid cells in the adipose tissue of CCR2-deficient mice delays improvements in insulin sensitivity.

OBJECTIVE: Mice with CCR2 deficiency are protected from insulin resistance but only after long periods of high-fat diet (HFD) feeding, despite the virtual absence of circulating inflammatory monocytes. We performed a time course study in mice with hematopoietic and global CCR2 deficiency to determine adipose tissue-specific mechanisms for the delayed impact of CCR2 deficiency on insulin resistance. RESEARCH DESIGN AND METHODS: Mice with global or hematopoietic CCR2 deficiency (CCR2(-/-) and BM-CCR2(-/-), respectively) and wild-type controls (CCR2(+/+) and BM-CCR2(+/+), respectively) were placed on an HFD for 6, 12, and 20 weeks. Adipose tissue myeloid populations, degree of inflammation, glucose tolerance, and insulin sensitivity were assessed. RESULTS: Flow cytometry analysis showed that two different populations of F4/80(+) myeloid cells (CD11b(lo)F4/80(lo) and CD11b(hi)F4/80(hi)) accumulated in the adipose tissue of CCR2(-/-) and BM-CCR2(-/-) mice after 6 and 12 weeks of HFD feeding, whereas only the CD11b(hi)F4/80(hi) population was detected in the CCR2(+/+) and BM-CCR2(+/+) controls. After 20 weeks of HFD feeding, the CD11b(lo)F4/80(lo) cells were no longer present in the adipose tissue of CCR2(-/-) mice, and only then were improvements in adipose tissue inflammation detected. Gene expression and histological analysis of the CD11b(lo)F4/80(lo) cells indicated that they are a unique undifferentiated monocytic inflammatory population. The CD11b(lo)F4/80(lo) cells are transiently found in wild-type mice, but CCR2 deficiency leads to the aberrant accumulation of these cells in adipose tissue. CONCLUSIONS: The discovery of this novel adipose tissue monocytic cell population provides advances toward understanding the pleiotropic role of CCR2 in monocyte/macrophage accumulation and regulation of adipose tissue inflammation.

Adipose tissue recruitment of leukocytes.

PURPOSE OF REVIEW: In December of 2003, two seminal articles describing the presence of macrophages in obese adipose tissue were published. These adipose tissue macrophages (ATMs) are inflammatory and promote local and systemic insulin resistance. Due to the continuing rise in obesity around the world, understanding how these ATMs contribute to metabolic disorders is of much interest. RECENT FINDINGS: Chemokines have been extensively studied for their role in ATM recruitment. Deficiency or antagonism of chemokine receptors that interact with multiple chemokine ligands reduces ATM accumulation. ATMs are now defined as either classically (M1) or alternatively (M2) activated. Peroxisome proliferator-activated receptor activation and adiponectin promote an M2-polarized state resulting in improved insulin sensitivity. Finally, recent studies have provided evidence that T lymphocytes, natural killer T cells, mast cells, and B cells also enter adipose tissue and may interact with macrophages and adipocytes. SUMMARY: Literature published during the past year has shown that macrophage recruitment to adipose tissue is only one of the important mediators of obesity-related insulin resistance. The phenotype of ATMs and recruitment of other immune cells to the adipose tissue play key roles in the overall contribution of adipose tissue to systemic metabolic outcomes of obesity.

Neurochemical characterization of tyrosine hydroxylase-immunoreactive interneurons in the developing rat cerebral cortex.

Understanding the development of cortical interneuron phenotypic diversity is critical because interneuron dysfunction has been implicated in several neurodevelopmental disorders. Here, tyrosine hydroxylase (TH)-immunoreactive neurons in the developing and adult rat cortex were characterized in light of findings regarding interneuron neurochemistry and development. Cortical TH-immunoreactive neurons were first observed 2 weeks postnatally and peaked in number 3 weeks after birth. At subsequent ages, the number of these cell profiles was gradually reduced, and they were seen less frequently in adults. No DNA fragmentation or active caspase 3 was observed in cortical TH cells at any age examined, eliminating cell death as an explanation for the decrease in cell number. Although cortical TH cells reportedly fail to produce subsequent catecholaminergic enzymes, we found that the majority of these cells at all ages contained phosphorylated TH, suggesting that the enzyme may be active and producing L-DOPA as an end-product. Morphological criteria and colocalization of some TH cells with glutamic acid decarboxylase suggest that these cells are interneurons. Previously, parvalbumin, somatostatin, and calretinin were demonstrated in non-overlapping subsets of interneurons. Cortical TH neurons colocalized with calretinin but not with parvalbumin or somatostatin. These findings suggest that the transitory increase in TH cell number is not due to cell death but possibly due to alterations in the amount of detectable TH present in these cells, and that at least some cortical TH-producing interneurons belong to the calretinin-containing subset of interneurons that originate developmentally in the caudal ganglionic eminence.