IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.

While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.

Glucocorticoid modulates oxidative and thermogenic function of rat brown adipose tissue and human brown adipocytes.

Chronic and excessive glucocorticoid (GC) exposure can cause Cushing's syndrome, resulting in fat accumulation in selected body areas. Particularly in the brown adipose tissue (BAT), GC acts negatively, resulting in whitening of the tissue. We hypothesized that dysregulation of microRNAs by GC could be an additional mechanism to explain its negative actions in BAT. Male Wistar rats were divided into two groups: (1) Control sham and (2) GC group that was administered dexamethasone 6.25 mg/200 µL via osmotic pump implantation over 28 days. After this period, the animals were euthanized and BAT tissue was properly stored. Human fat cells treated with dexamethasone were used to translate the experimental results found in animals to human biology. GC-treated rat BAT presented with large lipid droplets, severely impaired thermogenic activation, and reduced glucose uptake measured by 18F-FDG PET/CT. GC exposure induced a reduction in the mitochondrial OXPHOS system and oxygen consumption. MicroRNA profiling of BAT revealed five top-regulated microRNAs and among them miR-21-5p was the most significantly upregulated in GC-treated rats compared to the control group. Although upregulation of miR-21-5p in the tissue, differentiated primary brown adipocytes from GC-treated rats had decreased miR-21-5p levels compared to the control group. To translate these results to the clinic, human brown adipocytes were treated with dexamethasone and miR-21-5p inhibitor. In human brown cells, inhibition of miR-21-5p increased brown adipocyte differentiation and prevented GC-induced glucose uptake, resulting in a lower glycolysis rate. In conclusion, high-dose GC therapy significantly impacts brown adipose tissue function, with a notable association between glucose uptake and miR-21-5p.

Gene expression and characterization of clonally derived murine embryonic brown and brite adipocytes.

White adipocytes store energy, while brown and brite adipocytes release heat via nonshivering thermogenesis. In this study, we characterized two murine embryonic clonal preadipocyte lines, EB5 and EB7, each displaying unique gene marker expression profiles. EB5 cells differentiate into brown adipocytes, whereas EB7 cells into brite (also known as beige) adipocytes. To draw a comprehensive comparison, we contrasted the gene expression patterns, adipogenic capacity, as well as carbohydrate and lipid metabolism of these cells to that of F442A, a well-known white preadipocyte and adipocyte model. We found that commitment to differentiation in both EB5 and EB7 cells can be induced by 3-Isobutyl-1-methylxanthine/dexamethasone (Mix/Dex) and staurosporine/dexamethasone (St/Dex) treatments. Additionally, the administration of rosiglitazone significantly enhances the brown and brite adipocyte phenotypes. Our data also reveal the involvement of a series of genes in the transcriptional cascade guiding adipogenesis, pinpointing GSK3ß as a critical regulator for both EB5 and EB7 adipogenesis. In a developmental context, we observe that, akin to brown fat progenitors, brite fat progenitors make their appearance in murine development by 11-12 days of gestation or potentially earlier. This result contributes to our understanding of adipocyte lineage specification during embryonic development. In conclusion, EB5 and EB7 cell lines are valuable for research into adipocyte biology, providing insights into the differentiation and development of brown and beige adipocytes. Furthermore, they could be useful for the characterization of drugs targeting energy balance for the treatment of obesity and metabolic diseases.

Brown Adipose Tissue, Batokines, and Bioactive Compounds in Foods: An Update.

The discovery of metabolically active brown adipose tissue (BAT) in human adults and the worldwide increase in obesity and obesity-related chronic noncommunicable diseases (NCDs) has made BAT a therapeutic target in the last two decades. The potential of BAT to oxidize fatty acids rapidly and increase energy expenditure inversely correlates with adiposity, insulin and glucose resistance, and cardiovascular and metabolic diseases. Currently, BAT is recognized by a new molecular signature; several BAT-derived molecules that act positively on target tissues have been identified and collectively called batokines. Bioactive compounds present in foods are endowed with thermogenic properties that increase BAT activation signaling. Understanding the mechanisms that lead to BAT activation and the batokines secreted by it within the thermogenic state is fundamental for its recruitment and management of obesity and NCDs. This review contributes to recent updates on the morphophysiology of BAT, its endocrine role in obesity, and the main bioactive compounds present in foods involved in classical and nonclassical thermogenic pathways activation.

Cotadutide improves brown adipose tissue thermogenesis in obese mice.

We studied the effect of cotadutide, a dual agonist glucagon-like peptide 1 (GLP1)/Glucagon, on interscapular brown adipose tissue (iBAT) remodeling and thermogenesis of obese mice. Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Then, animals were redivided, adding cotadutide treatment: C, CC, HF, and HFC for four additional weeks. The multilocular brown adipocyte structure showed fat conversion (whitening), hypertrophy, and structural disarray in the HF group, which was reverted in cotadutide-treated animals. Cotadutide enhances the body temperature, thermogenesis, and sympathetic innervation (peroxisome proliferator-activated receptor-α, ß3 adrenergic receptor, interleukin 6, and uncoupled protein 1), reduces pro-inflammatory markers (disintegrin and metallopeptidase domain, morphogenetic protein 8a, and neuregulin 4), and improves angiogenesis (vascular endothelial growth factor A, and perlecan). In addition, cotadutide enhances lipolysis (perilipin and cell death-inducing DNA fragmentation factor α), mitochondrial biogenesis (nuclear respiratory factor 1, transcription factor A mitochondrial, mitochondrial dynamin-like GTPase, and peroxisome proliferator-activated receptor gamma coactivator 1α), and mitochondrial fusion/fission (dynamin-related protein 1, mitochondrial fission protein 1, and parkin RBR E3 ubiquitin protein ligase). Cotadutide reduces endoplasmic reticulum stress (activating transcription factor 4, C/EBP homologous protein, and growth arrest and DNA-damage inducible), and extracellular matrix markers (lysyl oxidase, collagen type I α1, collagen type VI α3, matrix metallopeptidases 2 and 9, and hyaluronan synthases 1 and 2). In conclusion, the experimental evidence is compelling in demonstrating cotadutide's thermogenic effect on obese mice's iBAT, contributing to unraveling its action mechanisms and the possible translational benefits.

Exercise prevents obesity by reducing gut-derived inflammatory signals to brown adipocytes in mice.

Gut dysbiosis impairs nonshivering thermogenesis (NST) in obesity. The antiobesogenic effects of exercise training might involve the modulation of gut microbiota and its inflammatory signals to the brown adipose tissue (BAT). This study evaluated whether high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) prevent overweight through reduced gut-derived inflammatory signals to BAT in high-fat-fed mice. Sixty male C57BL/6 mice (3 months old) comprised six experimental groups: control (C) diet group, C diet + HIIT (C-HIIT) group, C diet + MICT (C-MICT) group, high-fat (HF) diet group, HF diet + HIIT (HF-HIIT) group, and HF diet + MICT (HF-MICT) group. The protocols lasted for 10 weeks. HIIT and MICT restored body mass, mitigated glucose intolerance, and prevented hyperinsulinemia in HF-trained groups. A chronic HF diet caused dysbiosis, but HIIT and MICT prevented gut dysbiosis and preserved tight junction (TJ) gene expression. HF-HIIT and HF-MICT groups exhibited a similar pattern of goblet cell distribution, agreeing with the decreased plasma lipopolysaccharide concentrations and interscapular BAT (iBAT) Lbp-Cd14-Tlr4 expression. The lowered Nlrp3 and Il1ß in the HF-HITT and HF-MICT groups complied with iBAT thermogenic capacity maintenance. This study shows reliable evidence that HIIT and MICT prevented overweight by restoring the diversity of the gut microbiota phyla and TJ gene expression, thereby reducing inflammatory signals to brown adipocytes with preserved thermogenic capacity. Both exercise modalities prevented overweight, but HIIT rescued Zo-1 and Jam-a gene expression, exerting more potent anti-inflammatory effects than MICT (reduced LPS concentrations), providing a sustained increase in thermogenesis with 78% less distance traveled.

Peritumoral adipose tissue promotes lipolysis and white adipocytes browning by paracrine action.

Background: Stromal adipocytes and tumor breast epithelial cells undergo a mutual metabolic adaptation within tumor microenvironment. Therefore, browning and lipolysis occur in cancer associated adipocytes (CAA). However, the paracrine effects of CAA on lipid metabolism and microenvironment remodeling remain poorly understood. Methods: To analyze these changes, we evaluated the effects of factors in conditioned media (CM) derived from explants of human breast adipose tissue from tumor (hATT) or normal (hATN) on morphology, degree of browning, the levels of adiposity, maturity, and lipolytic-related markers in 3T3-L1 white adipocytes by Western blot, indirect immunofluorescence and lipolytic assay. We analyzed subcellular localization of UCP1, perilipin 1 (Plin1), HSL and ATGL in adipocytes incubated with different CM by indirect immunofluorescence. Additionally, we evaluated changes in adipocyte intracellular signal pathways. Results: We found that adipocytes incubated with hATT-CM displayed characteristics that morphologically resembled beige/brown adipocytes with smaller cell size and higher number of small and micro lipid droplets (LDs), with less triglyceride content. Both, hATT-CM and hATN-CM, increased Pref-1, C/EBPß LIP/LAP ratio, PPARγ, and caveolin 1 expression in white adipocytes. UCP1, PGC1α and TOMM20 increased only in adipocytes that were treated with hATT-CM. Also, hATT-CM increased the levels of Plin1 and HSL, while decreased ATGL. hATT-CM modified the subcellular localization of the lipolytic markers, favoring their relative content around micro-LDs and induced Plin1 segregation. Furthermore, the levels of p-HSL, p-ERK and p-AKT increased in white adipocytes after incubation with hATT-CM. Conclusions: In summary, these findings allow us to conclude that adipocytes attached to the tumor could induce white adipocyte browning and increase lipolysis as a means for endocrine/paracrine signaling. Thus, adipocytes from the tumor microenvironment exhibit an activated phenotype that could have been induced not only by secreted soluble factors from tumor cells but also by paracrine action from other adipocytes present in this microenvironment, suggesting a "domino effect".

Chronic Excessive Fructose Intake Maximizes Brown Adipocyte Whitening but Causes Similar White Adipocyte Hypertrophy Than a High-Fat Diet in C57BL/6 Mice.

Objective: This study aimed to evaluate the differential role of a high-fat diet (HF) or high-fructose diet (HFRU) on white adipose tissue and brown adipose tissue remodeling in C57BL/6 mice.Methods: The animals were randomly assigned to receive HF (50% of energy as lipids), HFRU (50% of energy as fructose), or a control diet (C, 10% of energy as lipids) for 12 weeks. Results: The HF group became overweight from the 7th week onwards, but both HF and HFRU groups showed hyperinsulinemia, oral glucose intolerance, and adverse adipose tissue remodeling. HF and HFRU groups showed interscapular brown adipose tissue whitening, tough the reduced QA [nuclei] suggested maximized brown adipocyte dysfunction due to the HFRU diet. In contrast, HF and HFRU diets exerted similar effects upon subcutaneous white adipocytes, with a similar average cross-sectional area. Immunohistochemistry confirmed the whitening enhancement with reduced UCP1 immunodensity in the HFRU group. Conclusion: In conclusion, HF and HFRU diets had indistinguishable effects upon white adipocyte morphology, but the HFRU diet provoked a more pronounced whitening than the HF diet after a 12-week protocol. These results point to the silent and harmful impact that excessive fructose has upon the metabolism of lean mice.

Brown adipose tissue as an endocrine organ: updates on the emerging role of batokines.

Brown adipose tissue (BAT) remains active in adults, oxidizing fatty acids or glucose and releasing energy in the form of heat. Brown adipocytes and enhanced thermogenesis are targets for treating obesity and its comorbidities. BAT shows high synthesis activity and secretes several signaling molecules. The brown adipokines, or batokines, take action in an autocrine, paracrine, and endocrine manner. Batokines have a role in the homeostasis of the cardiovascular system, central nervous system, white adipose tissue, liver, and skeletal muscle and exert beneficial effects on BAT. The systemic function of batokines gives BAT an endocrine organ profile. Besides, the batokines Fibroblast Growth Factor-21, Vascular Endothelial Growth Factor A, Bone Morphogenetic Protein 8, Neuregulin 4, Myostatin, and Interleukin-6 emerge as targets to treat obesity and its comorbidities, deserving attention. This review outlines the role of six emerging batokines on BAT and their cross-talk with other organs, focusing on their physiological significance and diet-induced changes.

Progressive brown adipocyte dysfunction: Whitening and impaired nonshivering thermogenesis as long-term obesity complications.

Chronic obesity damages the cytoarchitecture of brown adipose tissue (BAT), leading to whitening of brown adipocytes and impaired thermogenesis, characterizing BAT dysfunction. Understanding the pathways of whitening progression can bring new targets to counter obesity. This study aimed to evaluate the chronic effect (12, 16, and 20 weeks) of a high-fat diet (50% energy as fat) upon energy expenditure, thermogenic markers, and pathways involved in BAT whitening in C57BL/6J mice. Sixty adult male mice comprised six nutritional groups, where the letters refer to the diet type (control, C or high-fat, HF), and the numbers refer to the period (in weeks) of diet administration: C12, HF12, C16, HF16, C20, and HF20. After sacrifice, biochemical, molecular, and stereological analyses addressed the outcomes. The HF groups had overweight, oral glucose intolerance, and hyperleptinemia, resulting in progressive whitening of BAT and decreased numerical density of nuclei per area of tissue compared to age-matched control groups. In addition, the whitening maximization was related to altered batokines gene expression, decreased nonshivering thermogenesis, and body temperature, resulting in low energy expenditure. The HF20 group showed enlarged adipocytes with stable and dysfunctional lipid droplets, followed by inflammation and ER stress. In conclusion, chronic HF diet intake caused time-dependent maximization of whitening with defective nonshivering thermogenesis. Long-term BAT dysfunction includes down-regulated vascularization markers, upregulated inflammasome activation, and ER stress markers.

A PPAR-alpha agonist and DPP-4 inhibitor mitigate adipocyte dysfunction in obese mice.

Obesity causes white and brown adipocyte dysfunction, reducing browning and stimulating whitening. Drugs that tackle adipocyte dysfunction through thermogenesis stimulation could be used to treat obesity. This study sought to address whether a combination of the PPAR-alpha agonist (WY14643) and DPP4i (linagliptin) potentiates browning and mitigates adipose tissue dysfunction, emphasizing the pathways related to browning induction and the underlying thermogenesis in high-fat-fed mice. Adult male C57BL/6 mice were randomly assigned to receive a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for 12 weeks. Experiment 1 aimed to evaluate whether 5 weeks of combined therapy was able to potentiate browning using a five-group design: C, HF, HFW (monotherapy with WY14643, 2.5 mg/kg body mass), HFL (monotherapy with linagliptin, 15 mg/kg body mass), and HFC (a combination of both drugs). Experiment 2 further addressed the pathways involved in browning maximization using a four-group study design: C, CC (C diet plus the drug combination), HF, and HFC (HF diet plus the drug combination). The HF group showed overweight, oral glucose intolerance, sWAT adipocyte hypertrophy, and reduced numerical density of nuclei per area of BAT confirming whitening. Only the combined treatment normalized these parameters in addition to body temperature increase, browning induction, and whitening rescue. The high expression of thermogenic marker genes parallel to reduced expression of inflammatory and endoplasmic reticulum stress genes mediated the beneficial findings. Hence, the PPAR-alpha agonist and DPP-4i combination is a promising target for obesity control by inducing functional brown adipocytes, browning of sWAT, and enhanced adaptive thermogenesis.

Signaling Targets Related to Antiobesity Effects of Capsaicin: A Scoping Review.

The search for new antiobesogenic agents is increasing because of the current obesity pandemic. Capsaicin (Caps), an exogenous agonist of the vanilloid receptor of transient potential type 1 (TRPV1), has shown promising results in the treatment of obesity. This scoping review aims to verify the pathways mediating the effects of Caps in obesity and the different methods adopted to identify these pathways. The search was carried out using data from the EMBASE, MEDLINE (PubMed), Web of Science, and SCOPUS databases. Studies considered eligible evaluated the mechanisms of action of Caps in obesity models or cell types involved in obesity. Nine studies were included and 100% (n = 6) of the in vivo studies showed a high risk of bias. Of the 9 studies, 66.6% (n = 6) administered Caps orally in the diet and 55.5% (n = 5) used a concentration of Caps of 0.01% in the diet. In vitro, the most tested concentration was 1 µM (88.9%; n = 8). Capsazepine was the antagonist chosen by 66.6% (n = 6) of the studies. Seven studies (77.8%) linked the antiobesogenic effects of Caps to TRPV1 activation and 3 (33.3%) indicated peroxisome proliferator-activated receptor (PPAR) involvement as an upstream connection to TRPV1, rather than a direct metabolic target of Caps. The main secondary effects of Caps were lower weight gain (33.3%; n = 3) or loss (22.2%; n = 2), greater improvement in lipid profile (33.3%; n = 3), lower white adipocyte adipogenesis (33.3%; n = 3), browning process activation (44.4%; n = 4), and higher brown adipocyte activity (33.3%; n = 3) compared with those of the control treatment. Some studies have shown that PPAR agonists modulate TRPV1 activity, and no study has evaluated the simultaneous antagonism of these 2 receptors. Consequently, further studies are necessary to elucidate the role of each of these signaling molecules in the antiobesogenic effects of Caps.

Papel de la célula grasa en el riesgo cardiovascular / Role of the fat cell in cardiovascular risk

Resumen La obesidad es una enfermedad crónica, no transmisible, que recientemente ha tenido una connotación especial debido al aumento de su prevalencia en países en vía de desarrollo. Este incremento está relacionado con un aumento en la aparición de enfermedades metabólicas y el riesgo cardiovascular. Si bien la prevalencia de obesidad está aumentando en todos los países del mundo, existen diferencias regionales tanto en la prevalencia como en las tendencias de la obesidad. Por consiguiente, comprender los impulsores de estas diferencias regionales podría ayudar a proporcionar orientación para las estrategias de intervención más prometedoras. A pesar de considerarse una eventualidad simple en una proporción de lo que se ingiere y lo que se gasta, existen muchos factores que regulan esta enfermedad. No es sencillo encontrar medidas terapéuticas para la obesidad, pues sus causas son múltiples. En forma reciente, ha despertado un especial interés la caracterización funcional de los adipocitos, específicamente de los adipocitos beige, dado que su función está íntimamente relacionada con las circunstancias externas del ambiente y tienen una flexibilidad que les permite producir energía y mejorar muchos de los parámetros metabólicos en los individuos. En este manuscrito se hará énfasis en las características de las células adiposas y su influencia en el riesgo cardiovascular.

Abstract Obesity is a chronic non-transmissible disease that has recently had a special connotation due to the increase of its prevalence in developing countries. The increase in obesity is related to an expansion in the appearance of metabolic diseases and cardiovascular risk. Although the prevalence of obesity is increasing in all countries of the world, there are regional differences in both the prevalence and trends of obesity. Therefore, understanding the circumstances of these regional differences could help provide guidance for the most promising intervention strategies. Despite being considered a simple outcome in a proportion of what is ingested and what is spent, there are many factors that regulate this disease. It is not easy to find therapeutic measures for obesity, because their causes are multiple. Recently, the functional characterization of adipocytes, especially Beige adipocytes, has been of particular interest since their function is intimately related to the external circumstances of the environment and they have a flexibility that allows them to produce energy and improve many of the metabolic parameters in individuals. In the present manuscript we will focus on the characteristics of fat cells and their influence on cardiovascular risk.

The colors of adipose tissue and the relationship with irisin.

Excess adipose tissue is considered one of the main causes of metabolic and cardiovascular diseases. Initially, the adipose tissue was considered the main lipid and energy storage of the organism. Subsequently it was discovered that adipose tissue had other functions such as endocrine, controlling different metabolic and immune processes. Currently, different types of adipose tissue are recognized. The white adipocyte represents the main energy reserve, on the contrary the brown adipocyte is responsible for the oxidation of lipids for thermogenesis. The beige adipocyte originates from the white adipocyte, by a process known as "browning", which leads to lipolysis and thermogenesis. The 3 previous types have recently joined the blue adipocyte, which has a role in liver retinoid homeostasis and the pink adipocyte that participates in lactogenesis and is present in the mammary gland of animals; its role is still unknown in humans. The newly identified hormone Irisin is secreted by the skeletal muscle and promotes browning of white to beige adipose tissue, thus favoring thermogenesis. Another interesting aspect of this hormone is that it represents a connection between muscle activity and lipolysis. The above suggests that Irisin may be the key in the prevention and treatment of obesity.

El exceso de tejido adiposo representa una de las principales causas de las enfermedades metabólicas y cardiovasculares. Inicialmente al tejido adiposo se le consideró el almacén de lípidos y energía del organismo. Posteriormente se descubrió que presentaba otras funciones, como la endocrina, controlando diferentes procesos metabólicos e inmunitarios. Por sus características funcionales y estructurales, se reconocen varios tipos de tejido adiposo. El adipocito blanco representa la reserva energética y el adipocito marrón se encarga de la oxidación de los lípidos para la termogénesis. El adipocito beige se origina del adipocito blanco, mediante un proceso que conduce a la lipólisis y la termogénesis. A los anteriores se han sumado el adipocito azul, en el hígado, que interviene en la homeostasis de retinoides, y el adipocito rosa, que participa en la lactogénesis y se ha identificado en la glándula mamaria de animales. La irisina es una hormona secretada principalmente por el músculo esquelético, que promueve el pardeamiento del tejido adiposo blanco a beige, favoreciendo así la termogénesis. Otro aspecto interesante de esta hormona es que representa una conexión entre la actividad muscular y la lipólisis. Por lo anterior, la irisina puede ser una clave en la prevención y el tratamiento de la obesidad.

Lipidomics of brown and white adipose tissue: Implications for energy metabolism.

Adipose tissue exerts multiple vital functions that critically maintain energy balance, including storing and expending energy, as well as secreting factors that systemically modulate nutrient metabolism. Since lipids are the major constituents of the adipocytes, it is unsurprising that the lipid composition of these cells plays a critical role in maintaining their functions and communicating with other organs and cells. In both positive and negative energy balance conditions, lipids and free fatty acids secreted from adipocytes exert either beneficial or detrimental effects in other tissues, such as the liver, pancreas and muscle. The way the adipocytes communicate with other organs tightly depends on the nature of their lipidome composition. Notwithstanding, the lipidome composition of the adipocytes is affected by physiological factors such as adipocyte type, gender and age, but also by environmental cues such as diet composition, thermal stress and physical activity. Here we provide an updated overview on how the adipose tissue lipidome profile is shaped by different physiological and environmental factors and how these changes impact the way the adipocytes regulate whole-body energy metabolism.

Short-term exposure to air pollution (PM2.5) induces hypothalamic inflammation, and long-term leads to leptin resistance and obesity via Tlr4/Ikbke in mice.

A previous study demonstrated that a high-fat diet (HFD), administered for one-three-days, induces hypothalamic inflammation before obesity's established, and the long term affects leptin signaling/action due to inflammation. We investigate whether exposure to particulate matter of a diameter of ≤2.5 µm (PM2.5) in mice fed with a chow diet leads to similar metabolic effects caused by high-fat feeding. Compared to the filtered air group (FA), one-day-exposure-PM2.5 did not affect adiposity. However, five-days-exposure-PM2.5 increased hypothalamic microglia density, toll-like-receptor-4 (Tlr4), and the inhibitor-NF-kappa-B-kinase-epsilon (Ikbke) expression. Concurrently, fat mass, food intake (FI), and ucp1 expression in brown adipose tissue were also increased. Besides, decreased hypothalamic STAT3-phosphorylation and Pomc expression were found after twelve-weeks-exposure-PM2.5. These were accompanied by increased FI and lower energy expenditure (EE), leading to obesity, along with increased leptin and insulin levels and HOMA. Mechanistically, the deletion of Tlr4 or knockdown of the Ikbke gene in the hypothalamus was sufficient to reverse the metabolic outcomes of twelve-weeks-exposure-PM2.5. These data demonstrated that short-term exposure-PM2.5 increases hypothalamic inflammation, similar to a HFD. Long-term exposure-PM2.5 is even worse, leading to leptin resistance, hyperphagia, and decreased EE. These effects are most likely due to chronic hypothalamic inflammation, which is regulated by Tlr4 and Ikbke signaling.

Browning of the subcutaneous adipocytes in diet-induced obese mouse submitted to intermittent fasting.

PURPOSE: We studied subcutaneous white adipose tissue (sWAT) of obese mice submitted to intermittent fasting (IF). METHODS: Twelve-week-old C57BL/6 male mice received the diets Control (C) or high-fat (HF) for eight weeks (n = 20/each). Then, part of each group performed IF (24 h feeding/24 h fasting) for four weeks: C, C-IF, HF, and HF-IF (n = 10/each). RESULTS: Food intake did not show a difference in feeding and fasting days, but HF groups had a high energy intake. IF led to multilocular adipocytes in sWAT (browning), and improved respiratory quotient on the fed day. IF decreased gene expression of Leptin, but increased Adiponectin, ß3ar (beta3 adrenoreceptor), and Ucp1 (uncoupling protein). IF enhanced immunostaining of Caspase 3, Pcna (proliferating cell nuclear antigen), and UCP1 in sWAT. IF attenuated pro-inflammatory markers and pro-apoptotic markers in sWAT. CONCLUSIONS: IF in obese mice led to browning in sWAT adipocytes, enhanced thermogenesis, an improved adipose tissue pro-inflammatory profile.

The Impact of the Adipose Organ Plasticity on Inflammation and Cancer Progression.

Obesity is characterized by chronic and low-grade systemic inflammation, an increase of adipose tissue, hypertrophy, and hyperplasia of adipocytes. Adipose tissues can be classified into white, brown, beige and pink adipose tissues, which display different regulatory, morphological and functional characteristics of their adipocyte and immune cells. Brown and white adipocytes can play a key role not only in the control of energy homeostasis, or through the balance between energy storage and expenditure, but also by the modulation of immune and inflammatory responses. Therefore, brown and white adipocytes can orchestrate important immunological crosstalk that may deeply impact the tumor microenvironment and be crucial for cancer establishment and progression. Recent works have indicated that white adipose tissues can undergo a process called browning, in which an inducible brown adipocyte develops. In this review, we depict the mechanisms involved in the differential role of brown, white and pink adipocytes, highlighting their structural, morphological, regulatory and functional characteristics and correlation with cancer predisposition, establishment, and progression. We also discuss the impact of the increased adiposity in the inflammatory and immunological modulation. Moreover, we focused on the plasticity of adipocytes, describing the molecules produced and secreted by those cells, the modulation of the signaling pathways involved in the browning phenomena of white adipose tissue and its impact on inflammation and cancer.

High dose of linagliptin induces thermogenic beige adipocytes in the subcutaneous white adipose tissue in diet-induced obese C57BL/6 mice.

PURPOSE: To verify whether the treatment with linagliptin induces the browning of the subcutaneous WAT (sWAT) and thermogenesis in murine diet-induced obesity (DIO) model. METHODS: Forty animals were randomly assigned to receive a control diet (C, 10% lipids as energy) or a high-fat diet (HF, 50% lipids as energy) for 10 weeks. Each group was re-divided to begin the 5-week treatment, totalizing four experimental groups: C, C-L (C plus linagliptin, 30 mg/kg body mass; BM), HF, and HF-L (HF plus linagliptin, 30 mg/kg BM). The drug was mixed with diet. RESULTS: HF animals showed overweight, glucose intolerance, and a greater cross-sectional area of adipocytes. The treatment with linagliptin was able to normalize the BM, restore the glucose tolerance and the cross-sectional area of adipocytes. These observations comply with the observation of UCP1-positive multilocular adipocytes in the sWAT of treated animals. Both treated groups (C-L and HF-L) showed high expression of thermogenic and type 2 cytokines genes, which agree with the enhanced body temperature and the lower respiratory exchange ratio, implying enhanced thermogenesis with the use of lipids as fuel. CONCLUSIONS: The reduced BM, the enhanced body temperature, and the presence of positive UCP1 beige cells in the sWAT point to the activation of the browning cascade on the sWAT of linagliptin-treated mice, and hence, linagliptin could induce the thermogenic pathway as a pleiotropic effect that can have translational potential.

Nonalcoholic Fatty Liver Disease Progresses into Severe NASH when Physiological Mechanisms of Tissue Homeostasis Collapse.

Phenotypic modulation of NAFLD-severity by molecules derived from white (adipokines) and brown (batokines) adipose tissue may be important in inducing or protecting against the progression of the disease. Adipose tissue-derived factors can promote the progression of NAFLD towards severe histological stages (NASH-fibrosis and NASHcirrhosis). This effect can be modulated by the release of adipokines or batokines that directly trigger an inflammatory response in the liver tissue or indirectly modulate related phenotypes, such as insulin resistance. Metabolically dysfunctional adipose tissue, which is often infiltrated by macrophages and crown-like histological structures, may also show impaired production of anti-inflammatory cytokines, which may favor NAFLD progression into aggressive phenotypes by preventing its protective effects on the liver tissue.