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.

Purpose of Review In December of 2003, two seminal articles describing the presence of macrophages in obese adipose tissue (AT) were published. These AT 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. PPAR activation and adiponectin promote an M2 polarized state resulting in improved insulin sensitivity. Finally, recent studies have provided evidence that T lymphocytes, NKT cells, mast cells, and B cells also enter AT and may interact with macrophages and adipocytes. Summary Literature published during the past year has shown that macrophage recruitment to AT is only one of the important mediators of obesity-related insulin resistance. The phenotype of ATMs and recruitment of other immune cells to the AT play key roles in the overall contribution of AT to systemic metabolic outcomes of obesity.

OBJECTIVE Elevated serum free fatty acid (FFA) levels are associated with an increased risk for cardiovascular disease and type 2 diabetes. Macrophages are recruited to atherosclerotic plaques and metabolic tissues during obesity and accumulate lipids, including FFAs. We investigated the molecular consequences of intracellular saturated FFA accumulation in macrophages. METHODS AND RESULTS Previously, we demonstrated that co-treatment of mouse peritoneal macrophages (MPMs) with stearic acid and triacsin C (TC, an inhibitor of long-chain acyl-CoA synthetases) results in intracellular FFA accumulation and apoptosis. Here, we utilized Western blot analysis, real-time RT-PCR, and TUNEL staining to assess 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 pro-inflammatory M1 phenotype increases their susceptibility to inflammation and ER stress, but not apoptosis, in response to co-treatment with stearic acid and TC. 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.

OBJECTIVEMice 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 METHODSMice 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.RESULTSFlow cytometry analysis showed that two different populations of F4/80+ myeloid cells (CD11bloF4/80lo and CD11bhiF4/80hi) accumulated in the adipose tissue of CCR2−/− and BM-CCR2−/− mice after 6 and 12 weeks of HFD feeding, whereas only the CD11bhiF4/80hi population was detected in the CCR2+/+ and BM-CCR2+/+ controls. After 20 weeks of HFD feeding, the CD11bloF4/80lo 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 CD11bloF4/80lo cells indicated that they are a unique undifferentiated monocytic inflammatory population. The CD11bloF4/80lo cells are transiently found in wild-type mice, but CCR2 deficiency leads to the aberrant accumulation of these cells in adipose tissue.CONCLUSIONSThe 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.

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 THimmunoreactive neurons were first observed two weeks postnatally and peaked in number three 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 suggests that these cells are interneurons. Previously, parvalbumin, somatostatin, and calretinin were demonstrated in nonoverlapping 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.

A 71-year-old female patient was referred in 2013 for evaluation of an asymptomatic nonsecreting pituitary adenoma. The adenoma, measuring 13 mm in height by 10 mm in width, was discovered incidentally on imaging in 2012. Biochemical testing demonstrated a nonfunctioning adenoma. Given the relatively small lesion size and the lack of symptoms, observation was preferred over surgical intervention. The patient was monitored with routine MRI, which until 2016 demonstrated minimal growth. In early 2016, the patient developed recurrence of metastatic breast cancer and was treated with palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor. This inhibitor acts on a pathway believed to be involved in pituitary adenoma tumorigenesis. One year after starting palbociclib, routine imaging demonstrated significant regression of her pituitary adenoma. The authors hypothesize that inhibition of the CDK4/6 pathway by palbociclib contributed to adenoma regression in this patient, and that palbociclib may represent a possible adjuvant therapy for the treatment of nonfunctioning pituitary adenomas.

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