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.

Exceso de peso en España: situación actual, proyecciones para 2030 y sobrecoste directo estimado para el Sistema Nacional de Salud / Excess weight in Spain: current situation, projections for 2030, and estimated direct extra cost for the Spanish Health System

Introducción y objetivos: El exceso de peso potencia algunas enfermedades crónicas y reduce la calidad de vida, y su prevalencia crece en todo el mundo. El objetivo es estimar la evolución del exceso de peso entre 1987 y 2014 en población española adulta, calcular los casos de exceso de peso y sus sobrecostes médicos directos en 2006 y 2016, y proyectar su tendencia a 2030. Métodos: Se seleccionaron 47 artículos en una búsqueda bibliográfica sistemática para determinar la progresión de las prevalencias de sobrepeso, obesidad y obesidad mórbida y del índice de masa corporal promedio entre 1987 y 2014. Con estos datos, se estimó el número de casos en adultos españoles en 2006, 2016 y 2030 y sus sobrecostes directos. Resultados: Entre 1987 y 2014, las prevalencias de sobrepeso, obesidad y obesidad mórbida aumentaron el 0,28%/año (p=0,004), el 0,50%/año (p<0,001) y el 0,030%/año (p=0,006) en los varones y el 0,10%/año (p=0,123), el 0,25%/año (p=0,078) y el 0,042%/año (p=0,251) en las mujeres. El índice de masa corporal aumentó 0,10 puntos/año en varones (p<0,001) y 0,26 en mujeres (significativamente solo entre 1987-2002, p <0,001). Se estimaron 23.500.000 casos de exceso de peso en 2016, cuyo sobrecoste médico directo supuso 1.950.000.000 euros/año. De mantenerse la tendencia, entre 2016 y 2030 aparecerán 3.100.000 nuevos casos de exceso de peso, y se alcanzará en 2030 un sobrecoste médico directo de unos 3.000.000.000 euros/año. Conclusiones: El exceso de peso en los adultos en España aumenta desde que existen registros, y en 2016 supuso un sobrecoste directo del 2% del presupuesto sanitario. Con esta tendencia, en 2030 se habrá incrementado un 16% el número de casos y un 58% su sobrecoste sanitario directo

Introduction and objectives: Excess weight promotes the development of several chronic diseases and decreases quality of life. Its prevalence is increasing globally. Our aim was to estimate the trend in excess weight between 1987 and 2014 in Spanish adults, calculate cases of excess weight and its direct extra costs in 2006 and 2016, and project its trend to 2030. Methods: We selected 47 articles in a systematic literature search to determine the progression of the prevalence of overweight, nonmorbid obesity, and morbid obesity and average body mass index between 1987 and 2014. We projected the expected number of cases in 2006, 2016, and 2030 and the associated direct extra medical costs. Results: Between 1987 and 2014, the prevalence of overweight, obesity, and morbid obesity increased by 0.28%/y (P=.004), 0.50%/y (P <.001) and 0.030%/y (P=.006) in men, and by 0.10%/y (P=.123), 0.25%/y (P=.078), and 0.042%/y (P=.251) in women. The mean body mass index increased by 0.10 kg/m2/y in men (P <.001) and 0.26 kg/m2/y in women (significantly only between 1987 and 2002, P <.001). We estimated 23 500 000 patients with excess weight in 2016, generating 1.95 billion ⚬/y in direct extra medical costs. If the current trend continues, between 2016 and 2030, there will be 3 100 000 new cases of excess weight, leading to 3.0 billion ⚬/y of direct extra medical costs in 2030. Conclusions: Excess weight in Spanish adults has risen since the creation of population registries, generating direct extra medical costs that represent 2% of the 2016 health budget. If this trend continues, we expect 16% more cases in 2030 and 58% more direct extra medical costs

Brown Adipocytes Secrete GDF15 in Response to Thermogenic Activation.

OBJECTIVE: Transcriptomic analysis of gene expression in brown adipose tissue (BAT) from mice in response to cold revealed strong induction of growth and differentiation factor 15 (GDF15). This study aimed to characterize GDF15 as a brown adipokine released in response to thermogenic activation and to determine its target functions. METHODS: GDF15 expression was measured in adipose tissues from mice in response to physiological and pharmacological modulators of thermogenesis. Brown and beige cell cultures were used to dissect the mechanisms regulating GDF15 expression. Brown adipocyte cellular models of fibroblast growth factor 21 and ß-klotho invalidation were employed to identify the autocrine regulators of GDF15. RAW 264.7 macrophages were used to explore the targeting of GDF15 released by brown adipocytes. RESULTS: Cold exposure of mice strongly induced GDF15 expression in BAT. Norepinephrine and cyclic adenosine monophosphate induced GDF15 expression and release by cells through protein kinase A-mediated mechanisms. Noradrenergic regulation of GDF15 required the active fibroblast growth factor 21 pathway in brown adipocytes. GDF15 released by brown adipocytes targeted macrophages and downregulated the expression of proinflammatory genes. CONCLUSIONS: GDF15 is a brown adipokine released by brown and beige cells in response to thermogenic activity. GDF15 released by BAT targets macrophages and may mediate downregulation of local inflammatory pathways.

Excess Weight in Spain: Current Situation, Projections for 2030, and Estimated Direct Extra Cost for the Spanish Health System.

INTRODUCTION AND OBJECTIVES: Excess weight promotes the development of several chronic diseases and decreases quality of life. Its prevalence is increasing globally. Our aim was to estimate the trend in excess weight between 1987 and 2014 in Spanish adults, calculate cases of excess weight and its direct extra costs in 2006 and 2016, and project its trend to 2030. METHODS: We selected 47 articles in a systematic literature search to determine the progression of the prevalence of overweight, nonmorbid obesity, and morbid obesity and average body mass index between 1987 and 2014. We projected the expected number of cases in 2006, 2016, and 2030 and the associated direct extra medical costs. RESULTS: Between 1987 and 2014, the prevalence of overweight, obesity, and morbid obesity increased by 0.28%/y (P=.004), 0.50%/y (P <.001) and 0.030%/y (P=.006) in men, and by 0.10%/y (P=.123), 0.25%/y (P=.078), and 0.042%/y (P=.251) in women. The mean body mass index increased by 0.10 kg/m2/y in men (P <.001) and 0.26 kg/m2/y in women (significantly only between 1987 and 2002, P <.001). We estimated 23 500 000 patients with excess weight in 2016, generating 1.95 billion €/y in direct extra medical costs. If the current trend continues, between 2016 and 2030, there will be 3 100 000 new cases of excess weight, leading to 3.0 billion €/y of direct extra medical costs in 2030. CONCLUSIONS: Excess weight in Spanish adults has risen since the creation of population registries, generating direct extra medical costs that represent 2% of the 2016 health budget. If this trend continues, we expect 16% more cases in 2030 and 58% more direct extra medical costs.

Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue.

Fibroblast growth factor 21 (FGF21) has been proposed to be an antiaging hormone on the basis of experimental studies in rodent models. However, circulating FGF21 levels are increased with aging in rodents and humans. Moreover, despite the metabolic health-promoting effects of FGF21, the levels of this hormone are increased under conditions such as obesity and diabetes, an apparent incongruity that has been attributed to altered tissue responsiveness to FGF21. Here, we investigated serum FGF21 levels and expression of genes encoding components of the FGF21-response molecular machinery in adipose tissue from healthy elderly individuals (≥70 years old) and young controls. Serum FGF21 levels were increased in elderly individuals and were positively correlated with insulinemia and HOMA-IR, indices of mildly deteriorated glucose homeostasis. Levels of ß-Klotho, the coreceptor required for cellular responsiveness to FGF21, were increased in subcutaneous adipose tissue from elderly individuals relative to those from young controls, whereas FGF receptor-1 levels were unaltered. Moreover, total ERK1/2 protein levels were decreased in elderly individuals in association with an increase in the ERK1/2 phosphorylation ratio relative to young controls. Adipose explants from aged and young mice respond similarly to FGF21 "ex vivo". Thus, in contrast to what is observed in obesity and diabetes, high levels of FGF21 in healthy aging are not associated with repressed FGF21-responsiveness machinery in adipose tissue. The lack of evidence for impaired FGF21 responsiveness in adipose tissue establishes a distinction between alterations in the FGF21 endocrine system in aging and chronic metabolic pathologies.

Reciprocal Effects of Antiretroviral Drugs Used To Treat HIV Infection on the Fibroblast Growth Factor 21/ß-Klotho System.

Following antiretroviral therapy, HIV-infected patients show increased circulating levels of the antidiabetic hormone fibroblast growth factor 21 (FGF21). In contrast, the expression of the FGF21-obligatory coreceptor ß-Klotho (KLB) is reduced in target tissues. This situation is comparable to the FGF21 resistance status observed in obesity and type 2 diabetes. Here, we performed the first systematic study of the effects of distinct members of different antiretroviral drug classes on the FGF21/KLB system in human hepatic, adipose, and skeletal muscle cells. Most protease inhibitors and the nonnucleoside reverse transcriptase inhibitor efavirenz induced FGF21 gene expression. Neither nucleoside reverse transcriptase inhibitors nor the viral entry inhibitor maraviroc had any effect. Among the integrase inhibitors, elvitegravir significantly induced FGF21 expression, whereas raltegravir had minor effects only in adipose cells. In human hepatocytes and adipocytes, known target cells of FGF21 action, efavirenz, elvitegravir, and the lopinavir-ritonavir combination exerted inhibitory effects on KLB gene expression. Drug treatments that elicited FGF21 induction/KLB repression were those found to induce endoplasmic reticulum (ER) stress and oxidative stress. Notably, the pharmacological agents thapsigargin and tunicamycin, which induce these stress pathways, mimicked the effects of drug treatments. Moreover, pharmacological inhibitors of either ER or oxidative stress significantly impaired lopinavir-ritonavir-induced regulation of FGF21, but not KLB. In conclusion, the present in vitro screen study identifies the antiretroviral drugs that affect FGF21/KLB expression in human cells. The present results could have important implications for the management of comorbidities resulting from side effects of specific antiretroviral drugs for the treatment of HIV-infected patients.

The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes.

The thermogenic activity of brown adipose tissue (BAT) and browning of white adipose tissue are important components of energy expenditure. Here we show that GPR120, a receptor for polyunsaturated fatty acids, promotes brown fat activation. Using RNA-seq to analyse mouse BAT transcriptome, we find that the gene encoding GPR120 is induced by thermogenic activation. We further show that GPR120 activation induces BAT activity and promotes the browning of white fat in mice, whereas GRP120-null mice show impaired cold-induced browning. Omega-3 polyunsaturated fatty acids induce brown and beige adipocyte differentiation and thermogenic activation, and these effects require GPR120. GPR120 activation induces the release of fibroblast growth factor-21 (FGF21) by brown and beige adipocytes, and increases blood FGF21 levels. The effects of GPR120 activation on BAT activation and browning are impaired in FGF21-null mice and cells. Thus, the lipid sensor GPR120 activates brown fat via a mechanism that involves induction of FGF21.

Impact of elvitegravir on human adipocytes: Alterations in differentiation, gene expression and release of adipokines and cytokines.

Elvitegravir is a recently developed integrase inhibitor used for antiretroviral treatment of HIV infection. Secondary effects, including disturbances in lipid metabolism and, ultimately, in adipose tissue distribution and function, are common concerns associated with antiretroviral treatments. Here, we provide the first study of the effects of elvitegravir (in comparison with efavirenz, a non-nucleoside analog inhibitor of reverse transcriptase; and raltegravir, another integrase inhibitor) on human adipocyte differentiation, gene expression and secretion of adipokines and cytokines. Elvitegravir impaired adipogenesis and adipocyte metabolism in human SGBS adipocytes in a concentration-dependent manner (delaying acquisition of adipocyte morphology and reducing the expression of adipogenesis marker genes such as PPARγ, glucose transporter GLUT4, lipoprotein lipase, and the adipokines adiponectin and leptin). Compared with efavirenz, the effects of elvitegravir were similar but tended to occur at higher concentrations than those elicited by efavirenz, or were somewhat less intense than those caused by efavirenz at similar concentration. Elvitegravir tended to cause a more moderate induction of pro-inflammatory cytokines than efavirenz. Efavirenz induced a marked concentration-dependent increase in interleukin-8 expression and release whereas elvitregravir had little effect. Raltegravir had totally neutral actions of adipogenesis, adipocyte metabolism-related gene expression and release of adipokines and cytokines. In conclusion, elvitegravir alters adipocyte differentiation and function and promotes induction of pro-inflammatory cytokines similarly to efavirenz, but several effects were less intense. Further assessment of lipid metabolism and adipose tissue function in patients administered elvitegravir-based regimes is advisable considering that totally neutral effects of elvitegravir on lipid homeostasis cannot be anticipated from the current study in vitro.

The Molecular Signature of HIV-1-Associated Lipomatosis Reveals Differential Involvement of Brown and Beige/Brite Adipocyte Cell Lineages.

Highly active antiretroviral therapy has remarkably improved quality of life of HIV-1-infected patients. However, this treatment has been associated with the so-called lipodystrophic syndrome, which conveys a number of adverse metabolic effects and morphological alterations. Among them, lipoatrophy of subcutaneous fat in certain anatomical areas and hypertrophy of visceral depots are the most common. Less frequently, lipomatous enlargements of subcutaneous fat at distinct anatomic areas occur. Lipomatous adipose tissue in the dorso-cervical area ("buffalo hump") has been associated with a partial white-to-brown phenotype transition and with increased cell proliferation, but, to date, lipomatous enlargements arising in other parts of the body have not been characterized. In order to establish the main molecular events associated with the appearance of lipomatosis in HIV-1 patients, we analyzed biopsies of lipomatous tissue from "buffalo hump" and from other anatomical areas in patients, in comparison with healthy subcutaneous adipose tissue, using a marker gene expression approach. Both buffalo-hump and non-buffalo-hump lipomatous adipose tissues exhibited similar patterns of non-compromised adipogenesis, unaltered inflammation, non-fibrotic phenotype and proliferative activity. Shorter telomere length, prelamin A accumulation and SA-ß-Gal induction, reminiscent of adipocyte senescence, were also common to both types of lipomatous tissues. Buffalo hump biopsies showed expression of marker genes of brown adipose tissue (e.g. UCP1) and, specifically, of "classical" brown adipocytes (e.g. ZIC1) but not of beige/brite adipocytes. No such brown fat-related gene expression occurred in lipomatous tissues at other anatomical sites. In conclusion, buffalo hump and other subcutaneous adipose tissue enlargements from HIV-1-infected patients share a similar lipomatous character. However, a distorted induction of white-to-"classical brown adipocyte" phenotype appears unique of dorso-cervical lipomatosis. Thus, the insults caused by HIV-1 viral infection and/or antiretroviral therapy leading to lipomatosis are acting in a location- and adipocyte lineage-dependent manner.