A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity.

In obesity, inflammation of white adipose tissue (AT) is associated with diminished generation of beige adipocytes ('beige adipogenesis'), a thermogenic and energy-dissipating function mediated by beige adipocytes that express the uncoupling protein UCP1. Here we delineated an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated by the integrin α4 and its counter-receptor VCAM-1, respectively; expression of the latter was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation of macrophages and downregulation of UCP1 expression dependent on the kinase Erk in adipocytes. Genetic or pharmacological inactivation of the integrin α4 in mice resulted in elevated expression of UCP1 and beige adipogenesis of subcutaneous AT in obesity. Our findings, established in both mouse systems and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.

The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.

White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We will discuss the interactions of macrophages with other cell partners in WAT including adipose stem cells, adipocytes, and T cells in the context of various microenvironment niches in lean or obese condition. Finally, we highlight how adipose tissue macrophages merge immunity and metabolic changes to govern energy balance for the organism.

White Adipose Tissue Is a Reservoir for Memory T Cells and Promotes Protective Memory Responses to Infection.

White adipose tissue bridges body organs and plays a fundamental role in host metabolism. To what extent adipose tissue also contributes to immune surveillance and long-term protective defense remains largely unknown. Here, we have shown that at steady state, white adipose tissue contained abundant memory lymphocyte populations. After infection, white adipose tissue accumulated large numbers of pathogen-specific memory T cells, including tissue-resident cells. Memory T cells in white adipose tissue expressed a distinct metabolic profile, and white adipose tissue from previously infected mice was sufficient to protect uninfected mice from lethal pathogen challenge. Induction of recall responses within white adipose tissue was associated with the collapse of lipid metabolism in favor of antimicrobial responses. Our results suggest that white adipose tissue represents a memory T cell reservoir that provides potent and rapid effector memory responses, positioning this compartment as a potential major contributor to immunological memory.

OMIP-104: A 30-color spectral flow cytometry panel for comprehensive analysis of immune cell composition and macrophage subsets in mouse metabolic organs.

Obesity-induced chronic low-grade inflammation, also known as metaflammation, results from alterations of the immune response in metabolic organs and contributes to the development of fatty liver diseases and type 2 diabetes. The diversity of tissue-resident leukocytes involved in these metabolic dysfunctions warrants an in-depth immunophenotyping in order to elucidate disease etiology. Here, we present a 30-color, full spectrum flow cytometry panel, designed to (i) identify the major innate and adaptive immune cell subsets in murine liver and white adipose tissues and (ii) discriminate various tissue-specific myeloid subsets known to contribute to the development of metabolic dysfunctions. This panel notably allows for distinguishing embryonically-derived liver-resident Kupffer cells from newly recruited monocyte-derived macrophages and KCs. Furthermore, several adipose tissue macrophage (ATM) subsets, including perivascular macrophages, lipid-associated macrophages, and pro-inflammatory CD11c+ ATMs, can also be identified. Finally, the panel includes cell-surface markers that have been associated with metabolic activation of different macrophage and dendritic cell subsets. Altogether, our spectral flow cytometry panel allows for an extensive immunophenotyping of murine metabolic tissues, with a particular focus on metabolically-relevant myeloid cell subsets, and can easily be adjusted to include various new markers if needed.

White, brown, and beige; type 2 immunity gets hot.

The biogenesis of beige fat is poorly understood. In recent issues of Nature and Cell, Brestoff et al. (2014) and Lee et al. (2015) demonstrate that resident innate lymphoid cells in subcutaneous fat generate and activate beige adipocytes, producing thermogenesis.

Leukocyte Heterogeneity in Adipose Tissue, Including in Obesity.

Adipose tissue (AT) plays a central role in both metabolic health and pathophysiology. Its expansion in obesity results in increased mortality and morbidity, with contributions to cardiovascular disease, diabetes mellitus, fatty liver disease, and cancer. Obesity prevalence is at an all-time high and is projected to be 50% in the United States by 2030. AT is home to a large variety of immune cells, which are critical to maintain normal tissue functions. For example, γδ T cells are fundamental for AT innervation and thermogenesis, and macrophages are required for recycling of lipids released by adipocytes. The expansion of visceral white AT promotes dysregulation of its immune cell composition and likely promotes low-grade chronic inflammation, which has been proposed to be the underlying cause for the complications of obesity. Interestingly, weight loss after obesity alters the AT immune compartment, which may account for the decreased risk of developing these complications. Recent technological advancements that allow molecular investigation on a single-cell level have led to the discovery of previously unappreciated heterogeneity in many organs and tissues. In this review, we will explore the heterogeneity of immune cells within the visceral white AT and their contributions to homeostasis and pathology.

Regulatory T cells promote adipocyte beiging in subcutaneous adipose tissue.

Regulatory T cells (Tregs) play essential roles in obesity and diabetes. Here, we report a role of Tregs in enhancing ß3-adrenergic receptor agonist CL316243 (CL)-stimulated thermogenic program in subcutaneous adipose tissue (SAT), but not in visceral fat. CL treatment for 7 days increased SAT adipocyte beiging and thermogenic gene expression in male or female mice. Adoptive transfer of Tregs enhanced this CL activity. Such Treg activity lost in male epididymal white adipose tissue (eWAT) and female gonadal gWAT. Adipocyte culture yielded the same conclusion. Tregs enhanced the expression of CL-induced thermogenic genes in SAT from male and female mice. This activity of Tregs reduced or disappeared in adipocytes from eWAT or gWAT. Both CL and Tregs induced much higher UCP-1 (uncoupling protein-1) expression in SAT from females than that from males. A mechanistic study demonstrated a role of Tregs in suppressing the expression of M1 macrophage markers (Tnfa, Il6, iNos, Ip10) and promoting the expression of M2 macrophage markers (Mrc1, Arg1, Il10) in bone-marrow-derived macrophages or in SAT from male or female mice. In female mice with pre-established obesity, Treg adoptive transfer reduced the gWAT weight in 2 weeks. Together with CL treatment, Treg adoptive transfer reduced the SAT weight and further improved CL-induced glucose metabolism and insulin sensitivity in female obese mice, but did not affect CL-induced body weight loss in male or female obese mice. This study revealed a predominant role of Tregs in female mice in promoting adipocyte beiging and thermogenesis in SAT, in part by slanting M2 macrophage polarization.

Lmo4-resistin signaling contributes to adipose tissue-liver crosstalk upon weight cycling.

Repeated cycles of weight loss and regain, known as weight cycling, is often seen when people try to lose weight. The exact pathophysiological effects and the underlying mechanisms of weight cycling remain largely unclear. Here, we report that weight cycling induced by alternating feeding mice with a low-fat diet or a high-fat diet in a 1-week switch protocol caused further increased epididymal white adipose tissue (eWAT) weight, preadipocyte proliferation, hepatic inflammation, fasting blood glucose level, and glucose intolerance, compared with the continuously HF-fed mice. Combining the secretory protein database with RNA-sequencing and quantitative PCR (qPCR) results in eWAT, the mRNA levels of several adipokines, including Retn (encoding resistin), were found altered by weight cycling. A transcriptional co-factor Lmo4 was found regulated by weight cycling; Lmo4 enhanced preadipocyte proliferation, in vitro adipogenesis, transcription of Retn, and resistin secretion in 3T3-L1 cells. Primary mouse hepatocytes administrated with recombinant mouse resistin (rm-resistin), or exposed to media from Lmo4-overexpressed 3T3-L1 cells, showed increased inflammatory responses and gluconeogenesis. Furthermore, rm-resistin-injected normal chow-fed mice showed upregulated blood glucose level by increasing gluconeogenesis, and upregulated the hepatic inflammatory responses. Together, our results suggest a regulatory role of Lmo4-resistin signaling in weight cycling, indicating a crosstalk between the adipose tissue and liver.

Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity.

Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity and eosinophil and alternatively activated macrophage responses, and were recently identified in murine white adipose tissue (WAT) where they may act to limit the development of obesity. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)(+) beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signalling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that, in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.

Single cell approaches to address adipose tissue stromal cell heterogeneity.

A central function of adipose tissue is in the management of systemic energy homeostasis that is achieved through the co-ordinated regulation of energy storage and mobilization, adipokine release, and immune functions. With the dramatic increase in the prevalence of obesity and obesity-related metabolic disease over the past 30 years, there has been extensive interest in targeting adipose tissue for therapeutic benefit. However, in order for this goal to be achieved it is essential to establish a comprehensive atlas of adipose tissue cellular composition and define mechanisms of intercellular communication that mediate pathologic and therapeutic responses. While traditional methods, such as fluorescence-activated cell sorting (FACS) and genetic lineage tracing, have greatly advanced the field, these approaches are inherently limited by the choice of markers and the ability to comprehensively identify and characterize dynamic interactions among stromal cells within the tissue microenvironment. Single cell RNA sequencing (scRNAseq) has emerged as a powerful tool for deconvolving cellular heterogeneity and holds promise for understanding the development and plasticity of adipose tissue under normal and pathological conditions. scRNAseq has recently been used to characterize adipose stem cell (ASC) populations and has provided new insights into subpopulations of macrophages that arise during anabolic and catabolic remodeling in white adipose tissue. The current review summarizes recent findings that use this technology to explore adipose tissue heterogeneity and plasticity.

The involvement of neuroimmune cells in adipose innervation.

BACKGROUND: Innervation of adipose tissue is essential for the proper function of this critical metabolic organ. Numerous surgical and chemical denervation studies have demonstrated how maintenance of brain-adipose communication through both sympathetic efferent and sensory afferent nerves helps regulate adipocyte size, cell number, lipolysis, and 'browning' of white adipose tissue. Neurotrophic factors are growth factors that promote neuron survival, regeneration, and plasticity, including neurite outgrowth and synapse formation. Peripheral immune cells have been shown to be a source of neurotrophic factors in humans and mice. Although a number of immune cells reside in the adipose stromal vascular fraction (SVF), it has remained unclear what roles they play in adipose innervation. We previously demonstrated that adipose SVF secretes brain derived neurotrophic factor (BDNF). METHODS: We now show that deletion of this neurotrophic factor from the myeloid lineage of immune cells led to a 'genetic denervation' of inguinal subcutaneous white adipose tissue (scWAT), thereby causing decreased energy expenditure, increased adipose mass, and a blunted UCP1 response to cold stimulation. RESULTS: We and others have previously shown that noradrenergic stimulation via cold exposure increases adipose innervation in the inguinal depot. Here we have identified a subset of myeloid cells that home to scWAT upon cold exposure and are Ly6C+ CCR2+ Cx3CR1+ monocytes/macrophages that express noradrenergic receptors and BDNF. This subset of myeloid lineage cells also clearly interacted with peripheral nerves in the scWAT and were therefore considered neuroimmune cells. CONCLUSIONS: We propose that these myeloid lineage, cold induced neuroimmune cells (CINCs) are key players in maintaining adipose innervation as well as promoting adipose nerve remodeling under noradrenergic stimulation, such as cold exposure.

ErbB4 deletion predisposes to development of metabolic syndrome in mice.

ErbB4, a member of the EGF receptor family, plays a variety of roles in physiological and pathological states. Genetic studies have indicated a link between ErbB4 and type 2 diabetes and obesity, but its role in metabolic syndrome (MetS) has not been reported. In the current study we found that mice with ErbB4 deletion developed MetS after 24 wk on a medium-fat diet (MFD), as indicated by development of obesity, dyslipidemia, hepatic steatosis, hyperglycemia, hyperinsulinemia, and insulin resistance, compared with wild-type mice. ErbB4 deletion mice also exhibited increased amounts of subcutaneous and visceral fat, with increased serum leptin levels, compared with wild-type mice, whereas levels of adiponectin were not significantly different. Histologically, severe inflammation, indicated by F4/80 immunostaining and M1 macrophage polarization, was detected in inguinal and epididymal white adipose tissue in ErbB4 deletion mice. ErbB4 expression decreased during 3T3-L1 preadipocyte differentiation. Administration of neuroregulin 4, a specific ligand for ErbB4, to 3T3-L1 adipocytes had no effect on adipogenesis and lipolysis but significantly inhibited lipogenesis, promoted browning, induced GLUT4 redistribution to the cell membrane, and increased glucose uptake. Neuroregulin 4 also significantly increased glucose uptake in adipocytes isolated from wild-type mice, while these effects were significantly decreased in adipocytes isolated from ErbB4 deletion mice. In conclusion, our results indicate that ErbB4 may play an important role in glucose homeostasis and lipogenesis. ErbB4 deficiency-related obesity and adipose tissue inflammation may contribute to the development of MetS.

Global transcriptome analysis identifies weight regain-induced activation of adaptive immune responses in white adipose tissue of mice.

OBJECTIVE: Studies have indicated that weight regain following weight loss predisposes obese individuals to metabolic disorders; however, the molecular mechanism of this potential adverse effect of weight regain is not fully understood. Here we investigated global transcriptome changes and the immune response in mouse white adipose tissue caused by weight regain. DESIGN: We established a diet switch protocol to compare the effects of weight regain with those of weight gain without precedent weight loss, weight loss maintenance and chow diet. We conducted a time course analysis of global transcriptome changes in gonadal white adipose tissue (gWAT) during the weight fluctuation. Co-expression network analysis was used to identify functional modules associated with the weigh regain phenotype. Immune cell populations in gWAT were characterized by flow-cytometric immunophenotyping. Metabolic phenotypes were monitored by histological analysis of adipose tissue and liver, and blood-chemistry and body weight/composition analyses. RESULTS: In total, 952 genes were differentially expressed in the gWAT in the weight regain vs the weight gain group. Upregulated genes were associated with immune response and leukocyte activation. Co-expression network analysis showed that genes involved in major histocompatibility complex I and II-mediated antigen presentation and T-cell activation function were upregulated. Consistent with the transcriptome analysis results, flow cytometry demonstrated significant increases in subsets of T cells and proinflammatory M1 macrophages in the gWAT in the weight regain as compared to the weight gain group. In addition, upregulation of adaptive immune responses was associated with high incidence of adipocyte death and upregulation of high mobility group box 1, a well-known component of damage-associated molecular patterns. CONCLUSIONS: Our global transcriptome analysis identified weight regain-induced activation of adaptive immune responses in mouse white adipose tissue. Results suggest that activation of adipocyte death-associated adaptive immunity in adipose tissue may contribute to unfavorable metabolic effects of weight regain following weight loss.

Maternal vitamin D deficiency during pregnancy affects expression of adipogenic-regulating genes peroxisome proliferator-activated receptor gamma (PPARγ) and vitamin D receptor (VDR) in lean male mice offspring.

PURPOSE: Maternal vitamin D deficiency during pregnancy is a widespread issue that may have long-lasting consequences on offspring adiposity. We sought to determine how maternal vitamin D deficiency during the perinatal period would affect offspring adipose tissue development and gene expression. METHODS: Female C57BL/6 J mice were fed either a vitamin D deficient (VDD) or control diet from 4 weeks before pregnancy (periconception) until 7 days postparturition. Male offspring were weighed and euthanized at 75 days of age (early adult period), at which point serum was collected for biochemical analyses, and perigonadal and subcutaneous white adipose tissue (PGAT and SQAT, respectively) were excised, weighed, then flash-frozen for later histology and analyses of adipogenic gene expression. RESULTS: All adult male offspring were nonobese; there were no significant differences in body weight, adipose pad weight, or adipocyte size. However, VDD-exposed offspring had greater expression of the adipogenic-regulating genes peroxisome proliferator-activated receptor gamma (Pparg) and vitamin D receptor (Vdr). CONCLUSIONS: This study suggests that exposure to vitamin D deficiency during the perinatal period can directly affect genes involved in the development of adipose tissue in nonobese offspring. These novel findings invite further investigation into the mechanisms by which maternal vitamin D status during pregnancy affects adipose development and metabolic health of offspring.

Impairment of systemic DHA synthesis affects macrophage plasticity and polarization: implications for DHA supplementation during inflammation.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid obtained from the diet or synthesized from alpha-linolenic acid through the action of fatty acid elongases (ELOVL) and desaturases. DHA plays important roles in the central nervous system as well as in peripheral organs and is the precursor of several molecules that regulate resolution of inflammation. In the present study, we questioned whether impaired synthesis of DHA affected macrophage plasticity and polarization both in vitro and in vivo models. For this we investigated the activation status and inflammatory response of bone marrow-derived M1 and M2 macrophages obtained from mice deficient of Elovl2 (Elovl2-/-), a key enzyme for DHA synthesis in mammals. Although both wild type and Elovl2-/- mice were able to generate efficient M1 and M2 macrophages, M1 cells derived from Elovl2-/- mice showed an increased expression of key markers (iNOS, CD86 and MARCO) and cytokines (IL-6, IL-12 and IL-23). However, M2 macrophages exhibited upregulated M1-like markers like CD80, CD86 and IL-6, concomitantly with a downregulation of their signature marker CD206. These effects were counteracted in cells obtained from DHA-supplemented animals. Finally, white adipose tissue of Elovl2-/- mice presented an M1-like pro-inflammatory phenotype. Hence, impairment of systemic DHA synthesis delineates an alteration of M1/M2 macrophages both in vitro and in vivo, with M1 being hyperactive and more pro-inflammatory while M2 less protective, supporting the view that DHA has a key role in controlling the balance between pro- and anti-inflammatory processes.

Leucine and resistance training improve hyperglycemia, white adipose tissue loss, and inflammatory parameters in an experimental model of type 1 diabetes.

BACKGROUND: Loss of white adipose tissue (WAT), associated with type 1 diabetes (DM1), contributes to increased chronic systemic inflammation. AIM: The aim of this study was to investigate the effects of leucine supplementation and resistance training (RT) in attenuating WAT loss and improving inflammatory parameters and glucose metabolism in DM1 rats. METHODS: Thirty-two male Wistar rats were distributed into four groups: DA (sedentary and supplemented with non-essential amino acids (NEAA)), DL (sedentary and supplemented with leucine), DTA (submitted to RT and supplemented with NEAA) and DTL (submitted to RT and supplemented with leucine). DM1 was induced by streptozotocin (STZ). An 8-week period of RT consisted of climbing a ladder with a progressively increased load, and supplementation was offered in the feed. RESULTS: Glycemia, polyphagia and polydipsia were lower in DL, DTA and DTL groups compared with the DA group by approximately 20% ( p<.0001), 28% ( p=.004) and 64% ( p<.0001), respectively. Weight of total WAT and retroperitoneal adipose tissue (RPAT) were higher by approximately 21% ( p=.01) and 54% ( p=.0004), respectively, in DL, DTA and DTL groups compared with DA. However, gene expression of adiponectin and leptin in RPAT was only increased by RT (DTA and DTL) compared with DA and DL by approximately 93% ( p<.0001) and 78% ( p=.0002), respectively. Similarly, the levels of adiponectin in the serum, tissue IL-10 (RPAT) and serum IL-10 were only increased in DTA and DTL compared with DA and DL by approximately 31% ( p=.03), 45% ( p=.0009) and 35% ( p=.003), respectively. CONCLUSIONS: Both interventions, isolated or together, reduced hyperglycemia and excessive loss of WAT, but RT was the main factor responsible for attenuating inflammation.

[SECRETORY FUNCTION OF WHITE ADIPOSE TISSUE AND ADIPOKINES: BIOLOGICAL EFFECTS AND CLINICAL SIGNIFICANCE (REVIEW)].

In addition to accumulation and metabolism of triglycerides, white adipose tissue is recognized as the active endocrine organ, whose dysfunction is associated with the development of a wide range of diseases. The secretome of adipocytes is represented by a wide range of adipokines, which vary in depot and sex-specific manner. In addition, adipokines have diverse biological effects, correlations with different metabolic features and functions. In this review, the data on biological effects, origin and the clinical significance of adipokines are discussed. The influence of adipokines on metabolism, sensitivity to insulin, vascular homeostasis, angiogenesis, repair, inflammation and immune cells are shown. Visceral adipose tissue accumulation is accompanied with adipocytes hypertrophy and overproduction of such proinflammatory and proaterogenic molecules like resistin, visfatin, vaspin, tumor necrosis factor, interleukin 6, lipocalin, glypican 4, RBP4 etc. There is a tight correlation between these adipokines level and development of insulin resistance, type 2 diabetes, cardiometabolic complications and cancer. Thus, adipokines represent a group of informative biomarkers for the diagnostics of metabolic disorders and the prediction of the outcome of the wide range of diseases. The study of the effects and mechanisms of the action of adipokines is the basis for determining new targets for therapy.

Adrenomedullin 2 Enhances Beiging in White Adipose Tissue Directly in an Adipocyte-autonomous Manner and Indirectly through Activation of M2 Macrophages.

Adrenomedullin 2 (ADM2) is an endogenous bioactive peptide belonging to the calcitonin gene-related peptide family. Our previous studies showed that overexpression of ADM2 in mice reduced obesity and insulin resistance by increasing thermogenesis in brown adipose tissue. However, the effects of ADM2 in another type of thermogenic adipocyte, beige adipocytes, remain to be understood. The plasma ADM2 levels were inversely correlated with obesity in humans, and adipo-ADM2-transgenic (tg) mice displayed resistance to high-fat diet-induced obesity with increased energy expenditure. Beiging of subcutaneous white adipose tissues (WAT) was more noticeably induced in high-fat diet-fed transgenic mice with adipocyte-ADM2 overexpression (adipo-ADM2-tg mice) than in WT animals. ADM2 treatment in primary rat subcutaneous adipocytes induced beiging with up-regulation of UCP1 and beiging-related marker genes and increased mitochondrial uncoupling respiration, which was mainly mediated by activation of the calcitonin receptor-like receptor (CRLR)·receptor activity-modifying protein 1 (RAMP1) complex and PKA and p38 MAPK signaling pathways. Importantly, this adipocyte-autonomous beiging effect by ADM2 was translatable to human primary adipocytes. In addition, M2 macrophage activation also contributed to the beiging effects of ADM2 through catecholamine secretion. Therefore, our study reveals that ADM2 enhances subcutaneous WAT beiging via a direct effect by activating the CRLR·RAMP1-cAMP/PKA and p38 MAPK pathways in white adipocytes and via an indirect effect by stimulating alternative M2 polarization in macrophages. Through both mechanisms, beiging of WAT by ADM2 results in increased energy expenditure and reduced obesity, suggesting ADM2 as a novel anti-obesity target.

Increased adipose tissue aromatase activity improves insulin sensitivity and reduces adipose tissue inflammation in male mice.

Females are, in general, more insulin sensitive than males. To investigate whether this is a direct effect of sex-steroids (SS) in white adipose tissue (WAT), we developed a male mouse model overexpressing the aromatase enzyme, converting testosterone (T) to estradiol (E2), specifically in WAT (Ap2-arom mice). Adipose tissue E2 levels were increased while circulating SS levels were unaffected in male Ap2-arom mice. Importantly, male Ap2-arom mice were more insulin sensitive compared with WT mice and exhibited increased serum adiponectin levels and upregulated expression of Glut4 and Irs1 in WAT. The expression of markers of macrophages and immune cell infiltration was markedly decreased in WAT of male Ap2-arom mice. The adipogenesis was enhanced in male Ap2-arom mice, supported by elevated Pparg expression in WAT and enhanced differentiation of preadipocyte into mature adipocytes. In summary, increased adipose tissue aromatase activity reduces adipose tissue inflammation and improves insulin sensitivity in male mice. We propose that estrogen increases insulin sensitivity via a local effect in WAT on adiponectin expression, adipose tissue inflammation, and adipogenesis.

Nutrient Regulation: Conjugated Linoleic Acid's Inflammatory and Browning Properties in Adipose Tissue.

Obesity is the most widespread nutritional disease in the United States. Developing effective and safe strategies to manage excess body weight is therefore of paramount importance. One potential strategy to reduce obesity is to consume conjugated linoleic acid (CLA) supplements containing isomers cis-9, trans-11 and trans-10, cis-12, or trans-10, cis-12 alone. Proposed antiobesity mechanisms of CLA include regulation of (a) adipogenesis, (b) lipid metabolism, (c) inflammation, (d) adipocyte apoptosis, (e) browning or beiging of adipose tissue, and (f) energy metabolism. However, causality of CLA-mediated responses to body fat loss, particularly the linkage between inflammation, thermogenesis, and energy metabolism, is unclear. This review examines whether CLA's antiobesity properties are due to inflammatory signaling and considers CLA's linkage with lipogenesis, lipolysis, thermogenesis, and browning of white and brown adipose tissue. We propose a series of questions and studies to interrogate the role of the sympathetic nervous system in mediating CLA's antiobesity properties.