Parkin depletion prevents the age-related alterations in the FGF21 system and the decline in white adipose tissue thermogenic function in mice

Parkin is an ubiquitin‐E3 ligase that is involved in cellular mitophagy and was recently shown to contribute to controlling adipose tissue thermogenic plasticity. We found that Parkin expression is induced in brown (BAT) and white (WAT) adipose tissues of aged mice. We determined the potential role of Parkin in the aging-associated decline in the thermogenic capacity of adipose tissues by analyzing subcutaneous WAT, interscapular BAT, and systemic metabolic and physiological parameters in young (5 month-old) and aged (16 month-old) mice with targeted invalidation of the Parkin (Park2) gene, and their wild-type littermates. Our data indicate that suppression of Parkin prevented adipose accretion, increased energy expenditure and improved the systemic metabolic derangements, such as insulin resistance, seen in aged mice. This was associated with maintenance of browning and reduction of the age-associated induction of inflammation in subcutaneous WAT. BAT in aged mice was much less affected by Parkin gene invalidation. Such protection was associated with a dramatic prevention of the age-associated induction of fibroblast growth factor-21 (FGF21) levels in aged Parkin-invalidated mice. This was associated with a parallel reduction in FGF21 gene expression in adipose tissues and liver in aged Parkin-invalidated mice. Additionally, Parkin invalidation prevented the protein down-regulation of β-Klotho (a key co-receptor mediating FGF21 responsiveness in tissues) in aged adipose tissues. We conclude that Parkin down-regulation leads to improved systemic metabolism in aged mice, in association with maintenance of adipose tissue browning and FGF21 system functionality. (AU)

Parkin depletion prevents the age-related alterations in the FGF21 system and the decline in white adipose tissue thermogenic function in mice

Parkin is an ubiquitin‐E3 ligase that is involved in cellular mitophagy and was recently shown to contribute to controlling adipose tissue thermogenic plasticity. We found that Parkin expression is induced in brown (BAT) and white (WAT) adipose tissues of aged mice. We determined the potential role of Parkin in the aging-associated decline in the thermogenic capacity of adipose tissues by analyzing subcutaneous WAT, interscapular BAT, and systemic metabolic and physiological parameters in young (5 month-old) and aged (16 month-old) mice with targeted invalidation of the Parkin (Park2) gene, and their wild-type littermates. Our data indicate that suppression of Parkin prevented adipose accretion, increased energy expenditure and improved the systemic metabolic derangements, such as insulin resistance, seen in aged mice. This was associated with maintenance of browning and reduction of the age-associated induction of inflammation in subcutaneous WAT. BAT in aged mice was much less affected by Parkin gene invalidation. Such protection was associated with a dramatic prevention of the age-associated induction of fibroblast growth factor-21 (FGF21) levels in aged Parkin-invalidated mice. This was associated with a parallel reduction in FGF21 gene expression in adipose tissues and liver in aged Parkin-invalidated mice. Additionally, Parkin invalidation prevented the protein down-regulation of β-Klotho (a key co-receptor mediating FGF21 responsiveness in tissues) in aged adipose tissues. We conclude that Parkin down-regulation leads to improved systemic metabolism in aged mice, in association with maintenance of adipose tissue browning and FGF21 system functionality. (AU)

Parkin depletion prevents the age-related alterations in the FGF21 system and the decline in white adipose tissue thermogenic function in mice.

Parkin is an ubiquitin-E3 ligase that is involved in cellular mitophagy and was recently shown to contribute to controlling adipose tissue thermogenic plasticity. We found that Parkin expression is induced in brown (BAT) and white (WAT) adipose tissues of aged mice. We determined the potential role of Parkin in the aging-associated decline in the thermogenic capacity of adipose tissues by analyzing subcutaneous WAT, interscapular BAT, and systemic metabolic and physiological parameters in young (5 month-old) and aged (16 month-old) mice with targeted invalidation of the Parkin (Park2) gene, and their wild-type littermates. Our data indicate that suppression of Parkin prevented adipose accretion, increased energy expenditure and improved the systemic metabolic derangements, such as insulin resistance, seen in aged mice. This was associated with maintenance of browning and reduction of the age-associated induction of inflammation in subcutaneous WAT. BAT in aged mice was much less affected by Parkin gene invalidation. Such protection was associated with a dramatic prevention of the age-associated induction of fibroblast growth factor-21 (FGF21) levels in aged Parkin-invalidated mice. This was associated with a parallel reduction in FGF21 gene expression in adipose tissues and liver in aged Parkin-invalidated mice. Additionally, Parkin invalidation prevented the protein down-regulation of ß-Klotho (a key co-receptor mediating FGF21 responsiveness in tissues) in aged adipose tissues. We conclude that Parkin down-regulation leads to improved systemic metabolism in aged mice, in association with maintenance of adipose tissue browning and FGF21 system functionality.

The splicing factor SF3B1 is involved in brown adipocyte thermogenic activation.

The ability of alternative splicing mechanisms to control gene expression is increasingly being recognized as relevant for adipose tissue function. The expression of SF3B1, a key component of the SF3B complex directly involved in spliceosome formation, was previously reported to be significantly induced in brown adipose tissue under cold-induced thermogenic activation. Here, we identify that noradrenergic cAMP-mediated thermogenic stimulation increases SF3B1 expression in brown and beige adipocytes. We further show that pladienolide-B, a drug that binds SF3B1 to inhibit pre-mRNA splicing by targeting the SF3B complex, down-regulates key components of the thermogenic machinery (e.g., UCP1 gene expression), differentially alters the expression of alternative splicing-regulated transcripts encoding molecular actors involved in the oxidative metabolism of brown adipocytes (e.g., peroxisome proliferator-activated receptor-gamma co-activator-alpha [PGC-1α] and cytochrome oxidase subunit 7a genes), and impairs the respiratory activity of brown adipocytes. Similar alterations were found in brown adipocytes with siRNA-mediated knockdown of SF3B1 protein levels. Our findings collectively indicate that SF3B1 is a key factor in the appropriate thermogenic activation of differentiated brown adipocytes. This work exemplifies the importance of splicing processes in adaptive thermogenesis and suggests that pharmacological tools, such as pladienolide-B, may be used to modulate brown adipocyte thermogenic activity.

Adipose tissue plasticity in pheochromocytoma patients suggests a role of the splicing machinery in human adipose browning.

Adipose tissue from pheochromocytoma patients acquires brown fat features, making it a valuable model for studying the mechanisms that control thermogenic adipose plasticity in humans. Transcriptomic analyses revealed a massive downregulation of splicing machinery components and splicing regulatory factors in browned adipose tissue from patients, with upregulation of a few genes encoding RNA-binding proteins potentially involved in splicing regulation. These changes were also observed in cell culture models of human brown adipocyte differentiation, confirming a potential involvement of splicing in the cell-autonomous control of adipose browning. The coordinated changes in splicing are associated with a profound modification in the expression levels of splicing-driven transcript isoforms for genes involved in the specialized metabolism of brown adipocytes and those encoding master transcriptional regulators of adipose browning. Splicing control appears to be a relevant component of the coordinated gene expression changes that allow human adipose tissue to acquire a brown phenotype.

The Benefits of Dog-Assisted Therapy as Complementary Treatment in a Children's Mental Health Day Hospital.

Dog-assisted therapy (DAT) has shown benefits in people with mental health disorders. A child psychiatric day hospital would be a suitable setting to implement DAT and evaluate the benefits in a pediatric population. METHODS: Mixed methods research in a naturalistic setting was considered in this pre-post quantitative study including 23 children under 13 treated in a day hospital over 2 years. Quantitative analysis included the number of emotional and behavioral outbursts and attendance rate and self-control and social impairment questionnaires completed by family members and therapists. In the qualitative study, the experiences of 12 mental health professionals involved in DAT were documented through semi-structured interviews. RESULTS: On DAT days, there were fewer emotional and behavioral outbursts and higher attendance. Significant differences were obtained between pre- and post-test scores on the SCRS and the SRS-2 completed by the therapists, while no significant differences were obtained on the questionnaires completed by the parents. Observations based on the qualitative study were as follows: (1) DAT improves emotional self-regulation; (2) DAT could facilitate the work of therapists in day hospitals; (3) health professionals displayed uncertainty due to a lack of familiarity with DAT. CONCLUSIONS: DAT improved emotional self-regulation, attendance rate and self-control and social response in children with mental disorders attending a day hospital.

Downregulation of hepatic lipopolysaccharide binding protein improves lipogenesis-induced liver lipid accumulation.

Circulating lipopolysaccharide-binding protein (LBP) is increased in individuals with liver steatosis. We aimed to evaluate the possible impact of liver LBP downregulation using lipid nanoparticle-containing chemically modified LBP small interfering RNA (siRNA) (LNP-Lbp UNA-siRNA) on the development of fatty liver. Weekly LNP-Lbp UNA-siRNA was administered to mice fed a standard chow diet, a high-fat and high-sucrose diet, and a methionine- and choline-deficient diet (MCD). In mice fed a high-fat and high-sucrose diet, which displayed induced liver lipogenesis, LBP downregulation led to reduced liver lipid accumulation, lipogenesis (mainly stearoyl-coenzyme A desaturase 1 [Scd1]) and lipid peroxidation-associated oxidative stress markers. LNP-Lbp UNA-siRNA also resulted in significantly decreased blood glucose levels during an insulin tolerance test. In mice fed a standard chow diet or an MCD, in which liver lipogenesis was not induced or was inhibited (especially Scd1 mRNA), liver LBP downregulation did not impact on liver steatosis. The link between hepatocyte LBP and lipogenesis was further confirmed in palmitate-treated Hepa1-6 cells, in primary human hepatocytes, and in subjects with morbid obesity. Altogether, these data indicate that siRNA against liver Lbp mRNA constitutes a potential target therapy for obesity-associated fatty liver through the modulation of hepatic Scd1.

Differential effects of dolutegravir, bictegravir and raltegravir in adipokines and inflammation markers on human adipocytes.

AIMS: To assess the potential direct effects of the integrase strand-transfer inhibitors (INsTIs) dolutegravir, bictegravir, and raltegravir, drugs used as treatment for people living with human immunodeficiency virus (PLWH), on human adipose cells. MAIN METHODS: Drugs were added to the differentiation medium of human Simpson-Golabi-Behmel syndrome (SGBS) adipose cells and morphological adipogenesis was monitored for 10 days. Also, adipocytes were exposed to drugs following differentiation (day 14). The gene expression levels of selected adipogenesis markers, adipocyte metabolism markers, adipokines, and cytokines were determined by quantitative-reverse transcription polymerase-chain reaction. The release of adiponectin and leptin into the culture medium was measured using specific enzyme-linked immunosorbent assay, and release of interleukin-6 and chemokine (CC motif) ligand-2 using Multiplex assays. KEY FINDINGS: Overall morphological adipogenesis was unaltered by INsTIs. The expression of adipogenesis marker genes (peroxisome proliferator-activated receptor-Ɣ and lipoprotein lipase) was slightly reduced in dolutegravir-treated differentiating adipocytes. Bictegravir repressed gene expression and the release of pro-inflammatory cytokines in differentiating adipocytes. Dolutegravir and raltegravir increased interleukin-6 gene expression, but only dolutegravir increased interleukin-6 release. Dolutegravir repressed adiponectin expression and release in differentiating adipocytes and had a similar but milder effect on leptin. Drug treatment of mature adipocytes reduced adiponectin gene expression in response to dolutegravir. SIGNIFICANCE: The INsTIs studied do not have a significant effect on human adipose cell differentiation but exert distinct effects on gene expression and secretion of adipokines and cytokines. These findings will help understand and manage the effects of INsTI-containing treatments on body weight and metabolic dysregulation in PLWH.

Sexual Dimorphism in Brown Adipose Tissue Activation and White Adipose Tissue Browning.

The present narrative review gathers the studies reported so far, addressing sex differences in the effects of cold exposure, feeding pattern and age on brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. In rodents, when exposed to decreasing temperatures, females activate thermogenesis earlier. Results obtained in humans go in the same line, although they do not provide results as solid as those obtained in rodents. Regarding the effects of overfeeding, interesting sex differences on BAT thermogenic capacity have been reported, and the greater or lower sensitivity of each sex to this dietary situation seems to be dependent on the type of feeding. In the case of energy restriction, females are more sensitive than males. In addition, sex differences have also been observed in thermogenesis changes induced by phenolic compound administration. During sexual development, an increase in BAT mass and BAT activity takes place. This phenomenon is greater in boys than in girls, probably due to its relation to muscle-mass growth. The opposite situation takes place during ageing, a lifespan period where thermogenic capacity declines, this being more acute in men than in women. Finally, the vast majority of the studies have reported a higher susceptibility to developing WAT browning amongst females. The scarcity of results highlights the need for further studies devoted to analysing this issue, in order to provide valuable information for a more personalised approach.

The armadillo-repeat containing X-linked protein 3, ARMCX3, is a negative regulator of the browning of adipose tissue associated with obesity.

OBJECTIVES: To determine the role of armadillo repeat-containing X-linked protein 3 (ARMCX3) in the thermogenic plasticity of adipose tissue. METHODS: Adipose tissues were characterized in Armcx3-KO male mice. Armcx3 gene expression was analyzed in adipose tissue from mice exposed to thermogenic inducers (cold, ß3-adenergic stimulus) and in differentiating brown and beige cells in culture. Analyses encompassed circulating metabolite and hormonal profiling, tissue characterization, histology, gene expression patterns, and immunoblot assays. Armcx3 gene expression was assessed in subcutaneous adipose tissue from lean individuals and individuals with obesity and was correlated with expression of marker genes of adipose browning. The effects of adenoviral-mediated overexpression of ARMCX3 on differentiating brown adipocyte gene expression and respiratory activity were determined. RESULTS: Male mice lacking ARMCX3 showed significant induction of white adipose tissue browning. In humans, ARMCX3 expression in subcutaneous adipose tissue was inversely correlated with the expression of marker genes of thermogenic activity, including CIDEA, mitochondrial transcripts, and creatine kinase-B. Armcx3 expression in adipose tissues was repressed by thermogenic activation (cold or ß3-adrenergic stimulation) and was upregulated by obesity in mice and humans. Experimentally-induced increases in Armcx3 caused down-regulation of thermogenesis-related genes and reduced mitochondrial oxidative activity of adipocytes in culture, whereas siRNA-mediated Armcx3 knocking-down enhanced expression of thermogenesis-related genes. CONCLUSION: ARMCX3 is a novel player in the control of thermogenic adipose tissue plasticity that acts to repress acquisition of the browning phenotype and shows a direct association with indicators of obesity in mice and humans.

Downregulation of peripheral lipopolysaccharide binding protein impacts on perigonadal adipose tissue only in female mice.

BACKGROUND AND AIMS: The sexual dimorphism in fat-mass distribution and circulating leptin and insulin levels is well known, influencing the progression of obesity-associated metabolic disease. Here, we aimed to investigate the possible role of lipopolysaccharide-binding protein (LBP) in this sexual dimorphism. METHODS: The relationship between plasma LBP and fat mass was evaluated in 145 subjects. The effects of Lbp downregulation, using lipid encapsulated unlocked nucleomonomer agent containing chemically modified-siRNA delivery system, were evaluated in mice. RESULTS: Plasma LBP levels were associated with fat mass and leptin levels in women with obesity, but not in men with obesity. In mice, plasma LBP downregulation led to reduced weight, fat mass and leptin gain after a high-fat and high-sucrose diet (HFHS) in females, in parallel to increased expression of adipogenic and thermogenic genes in visceral adipose tissue. This was not observed in males. Plasma LBP downregulation avoided the increase in serum LPS levels in HFHS-fed male and female mice. Serum LPS levels were positively correlated with body weight and fat mass gain, and negatively with markers of adipose tissue function only in female mice. The sexually dimorphic effects were replicated in mice with established obesity. Of note, LBP downregulation led to recovery of estrogen receptor alpha (Esr1) mRNA levels in females but not in males. CONCLUSION: LBP seems to exert a negative feedback on ERα-mediated estrogen action, impacting on genes involved in thermogenesis. The known decreased estrogen action and negative effects of metabolic endotoxemia may be targeted through LBP downregulation.

Adipose tissue aging partially accounts for fat alterations in HIV lipodystrophy.

Lipodystrophy is a major disturbance in people living with HIV-1 (PLWH). Several systemic alterations in PLWH are reminiscent of those that occur in ageing. It is unknown whether the lipodystrophy in PLWH is the consequence of accelerated ageing in adipose tissue. We compared systemic and adipose tissue disturbances in PLWH with those in healthy elderly individuals (~80 y old). We observed similarly enhanced expression of inflammation-related genes and decreased autophagy in adipose tissues from elderly individuals and PLWH. Indications of repressed adipogenesis and mitochondrial dysfunction were found specifically in PLWH, whereas reduced telomere length and signs of senesce were specific to elderly individuals. We conclude that ageing of adipose tissue accounts only partially for the alterations in adipose tissues of PLWH.

Increased Circulating Levels of Growth Differentiation Factor 15 in Association with Metabolic Disorders in People Living with HIV Receiving Combined Antiretroviral Therapy.

OBJECTIVE: People living with HIV (PLWH) have an increased cardiovascular risk (CVR) owing to dyslipidemia, insulin resistance, metabolic syndrome, and HIV/combination antiretroviral therapy (cART)-associated lipodystrophy (HALS). Atherosclerosis and inflammation are related to growth differentiation factor-15 (GDF15). The relationship between metabolic disturbances, HALS, and CVR with GDF15 in PLWH is not known. RESEARCH DESIGN AND METHODS: Circulating GDF15 levels in 152 PLWH (with HALS = 60, without HALS = 43, cART-naïve = 49) and 34 healthy controls were assessed in a cross-sectional study. Correlations with lipids, glucose homeostasis, fat distribution, and CVR were explored. RESULTS: PLWH had increased circulating GDF15 levels relative to controls. The increase was the largest in cART-treated PLWH. Age, homeostatic model assessment of insulin resistance 1 (HOMA1-IR), HALS, dyslipidemia, C-reactive protein, and CVR estimated with the Framingham score correlated with GDF15 levels. The GDF15-Framingham correlation was lost after age adjustment. No correlation was found between GDF15 and the D:A:D Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) score estimated CVR. CVR independent predictors were patient group (naïve, HALS-, and HALS+) and cumulated protease inhibitor or nucleoside reverse transcriptase inhibitor exposure. CONCLUSIONS: PLWH, especially when cART-treated, has increased GDF15 levels-this increase is associated with dyslipidemia, insulin resistance, metabolic syndrome, HALS, and inflammation-related parameters. GDF15 is unassociated with CVR when age-adjusted.

Specific adipose tissue Lbp gene knockdown prevents diet-induced body weight gain, impacting fat accretion-related gene and protein expression.

Lipopolysaccharide binding protein (Lbp) has been recently identified as a relevant component of innate immunity response associated to adiposity. Here, we aimed to investigate the impact of adipose tissue Lbp on weight gain and white adipose tissue (WAT) in male and female mice fed an obesogenic diet. Specific adipose tissue Lbp gene knockdown was achieved through lentiviral particles containing shRNA-Lbp injected through surgery intervention. In males, WAT Lbp mRNA levels increased in parallel to fat accretion, and specific WAT Lbp gene knockdown led to reduced body weight gain, decreased fat accretion-related gene and protein expression, and increased inguinal WAT basal lipase activity, in parallel to lowered plasma free fatty acids, leptin, triglycerides but higher glycerol levels, resulting in slightly improved insulin action in the insulin tolerance test. In both males and females, inguinal WAT Lbp gene knockdown resulted in increased Ucp1 and Ppargc1a mRNA and Ucp1 protein levels, confirming adipose Lbp as a WAT browning repressor. In perigonadal WAT, Lbp gene knockdown also resulted in increased Ucp1 mRNA levels, but only in female mice, in which it was 500-fold increased. These data suggest specific adipose tissue Lbp gene knockdown as a possible therapeutic approach in the prevention of obesity-associated fat accretion.

The endocrine role of brown adipose tissue: An update on actors and actions.

In recent years, brown adipose tissue (BAT) has been recognized not only as a main site of non-shivering thermogenesis in mammals, but also as an endocrine organ. BAT secretes a myriad of regulatory factors. These so-called batokines exert local autocrine and paracrine effects, as well as endocrine actions targeting tissues and organs at a distance. The endocrine batokines include peptide factors, such as fibroblast growth factor-21 (FGF21), neuregulin-4 (NRG4), phospholipid transfer protein (PLTP), interleukin-6, adiponectin and myostatin, and also lipids (lipokines; e.g., 12,13-dihydroxy-9Z-octadecenoic acid [12,13-diHOME]) and miRNAs (e.g., miR-99b). The liver, heart, and skeletal muscle are the most commonly reported targets of batokines. In response to BAT thermogenic activation, batokines such as NRG4 and PLTP are released and act to reduce hepatic steatosis and improve insulin sensitivity. Stress-induced interleukin-6-mediated signaling from BAT to liver favors hepatic glucose production through enhanced gluconeogenesis. Batokines may act on liver to induce the secretion of regulatory hepatokines (e.g. FGF21 and bile acids in response to miR-99b and PLTP, respectively), thereby resulting in a systemic expansion of BAT-originating signals. Batokines also target extrahepatic tissues: FGF21 and 12,13-diHOME are cardioprotective, whereas BAT-secreted myostatin and 12,13-diHOME influence skeletal muscle development and performance. Further research is needed to ascertain in humans the role of batokines, which have been identified mostly in experimental models. The endocrine role of BAT may explain the association between active BAT and a healthy metabolism in the human system, which is characterized by small amounts of BAT and a likely moderate BAT-mediated energy expenditure.

A Differential Pattern of Batokine Expression in Perivascular Adipose Tissue Depots From Mice.

Depending on its anatomical placement, perivascular adipose tissue (PVAT) has been found to possess features more (e.g., aortic thoracic) or less (e.g., aortic abdominal) similar to brown/beige adipose tissue in mice, whereas PVAT surrounding the mesenteric arteries and the caudal part of abdominal aorta is similar to white fat. PVAT is thought to influence vascular function through the effects of adipose-secreted molecules on vessels. Brown adipose tissue was recently shown to play differential secretory role via secretion of the so-called batokines but the involvement of differential batokine production in PVAT brown/beige plasticity was unclear. The current study characterizes for the first time the expression of batokines at aortic thoracic PVAT (tPVAT) and aortic abdominal PVAT (aPVAT) in comparison with typical brown and white adipose depots, in basal and thermogenically activated conditions. We found that both PVAT depots increased their expression of genes encoding the batokines bone morphogenetic protein-8b (BMP8B), fibroblast growth factor-21 (FGF21), and kininogen-2 (KNG2) in response to cold, indicating that, under cold-induced thermogenic activation, both thoracic aorta and abdominal aorta would experience intense local exposure to these PVAT-secreted batokines. In contrast, the gene expression levels of growth/differentiation factor-15 and vascular endothelial growth factor-A were induced only in tPVAT. Under short-term high-fat diet-induced thermogenic activation, the thoracic aorta would be specifically exposed to a local increase in PVAT-originating BMP8B, FGF21, and KNG2. Our data support the notion that acquisition of a brown/beige phenotype in PVAT is associated with upregulation of batokines, mainly BMP8B, FGF21, and KNG2, that can differentially target the vascular system.

FGF21 serum levels are related to insulin resistance, metabolic changes and obesity in Mexican people living with HIV (PLWH).

BACKGROUND: Antiretroviral therapy has significantly improved prognosis in treatment against HIV infection, however, prolonged exposure is associated to cardiovascular diseases, lipodystrophy, type 2 diabetes, insulin resistance, metabolic alteration, as obesity which includes the accumulation of oxidative stress in adipose tissue. FGF21 is a peptide hormone that is known to regulate glucose and lipid metabolism. FGF21 is expressed and secreted primarily in the liver and adipose tissue, promoting oxidation of glucose/fatty acids and insulin sensitivity. Alterations in FGF21 may be associated with the development of insulin resistance, metabolic syndrome and cardiovascular disease. We hypothesized that FGF21 protein levels are associated with metabolic abnormalities, placing special attention to the alterations in relation to the concurrence of overweight/obesity in people living with HIV (PLWH). DESIGN: Serum FGF21 was analyzed in 241 subjects, 160 PLWH and 81 unrelated HIV-uninfected subjects as a control group. Clinical records were consulted to obtain CD4+ cell counting and number of viral RNA copies. Serum FGF21 levels were tested for correlation with anthropometric and metabolic parameters; glucose, cholesterol, HDL, LDL, VLDL, triglycerides, insulin and indexes of atherogenesis and insulin resistance (HOMA). RESULTS: The participants were classified into four groups: (i) PLWH with normal weight, (ii) PLWH with overweight/obesity, (iii) HIV-uninfected with normal weight, and (iv) HIV-uninfected with overweight/obesity. Insulin levels were higher in normal-weight PLWH than in the HIV-uninfected group but not statistically significant, however, for the overweight/obesity PLWH group, insulin levels were significantly higher in comparison with the other three groups (p<0.0001). For FGF21, serum levels were slightly higher in the overweight/obesity groups in both patients and controls. In HIV-infected subjects, FGF21 levels showed a strong positive correlation with triglycerides, insulin levels and insulin resistance with a p-value <0.0001. In the seronegative group, FGF21 was only correlated with weight and waist circumference, showing an important association of FGF21 levels with the degree of obesity of the individuals. CONCLUSION: Insulin resistance and FGF21 elevations were observed in overweight-obese PLWH. FGF21 elevation could be viewed as a compensation mechanism as, in the control group, FGF21 correlations appeared to be confined to weight and waist circumference. This can be explained based on the action of FGF21 promoting the uptake of glucose in adipose tissue. In PLWH, FGF21 was low, possibly as a result of a change in adiposity leading to a metabolic disruption.

Levels of ß-klotho determine the thermogenic responsiveness of adipose tissues: involvement of the autocrine action of FGF21.

Fibroblast growth factor-21 (FGF21) is a hormonal regulator of metabolism; it promotes glucose oxidation and the thermogenic capacity of adipose tissues. The levels of ß-klotho (KLB), the co-receptor required for FGF21 action, are decreased in brown (BAT) and white (WAT) adipose tissues during obesity, diabetes, and lipodystrophy. Reduced ß-klotho levels have been proposed to account for FGF21 resistance in these conditions. In this study, we explored whether downregulation of ß-klotho affects metabolic regulation and the thermogenic responsiveness of adipose tissues using mice with total (KLB-KO) or partial (KLB-heterozygotes) ablation of ß-klotho. We herein show that KLB gene dosage was inversely associated with adiposity in mice. Upon cold exposure, impaired browning of subcutaneous WAT and milder alterations in BAT were associated with reduced KLB gene dosage in mice. Cultured brown and beige adipocytes from mice with total or partial ablation of the KLB gene showed reduced thermogenic responsiveness to ß3-adrenergic activation by treatment with CL316,243, indicating that these effects were cell-autonomous. Deficiency in FGF21 mimicked the KLB-reduction-induced impairment of thermogenic responsiveness in brown and beige adipocytes. These results indicate that the levels of KLB in adipose tissues determine their thermogenic capacity to respond to cold and/or adrenergic stimuli. Moreover, an autocrine action of FGF21 in brown and beige adipocytes may account for the ability of the KLB level to influence thermogenic responsiveness.NEW & NOTEWORTHY Reduced levels of KLB (the obligatory FGF21 co-receptor), as occurring in obesity and type 2 diabetes, reduce the thermogenic responsiveness of adipose tissues in cold-exposed mice. Impaired response to ß3-adrenergic activation in brown and beige adipocytes with reduced KLB occurs in a cell-autonomous manner involving an autocrine action of FGF21.

Adipose tissue knockdown of lysozyme reduces local inflammation and improves adipogenesis in high-fat diet-fed mice.

Chronic systemic low-level inflammation in metabolic disease is known to affect adipose tissue biology. Lysozyme (LYZ) is a major innate immune protein but its role in adipose tissue has not been investigated. Here, we aimed to investigate LYZ in human and rodents fat depots, and its possible role in obesity-associated adipose tissue dysfunction. LYZ mRNA and protein were identified to be highly expressed in adipose tissue from subjects with obesity and linked to systemic chronic-low grade inflammation, adipose tissue inflammation and metabolic disturbances, including hyperglycemia, dyslipidemia and decreased markers of adipose tissue adipogenesis. These findings were confirmed in experimental models after a high-fat diet in mice and rats and also in ob/ob mice. Importantly, specific inguinal and perigonadal white adipose tissue lysozyme (Lyz2) gene knockdown in high-fat diet-fed mice resulted in improved adipose tissue inflammation in parallel to reduced lysozyme activity. Of note, Lyz2 gene knockdown restored adipogenesis and reduced weight gain in this model. In conclusion, altogether these observations point to lysozyme as a new actor in obesity-associated adipose tissue dysfunction. The therapeutic targeting of lysozyme production might contribute to improve adipose tissue metabolic homeostasis.