16α‐Bromoepiandrosterone as a new candidate for experimental diabetes‐tuberculosis comorbidity treatment

Tuberculosis (TB) is the leading cause of death from a single bacterial infectious agent and is one of the most relevant issues of public health. Another pandemic disease is type II diabetes mellitus (T2D) that is estimated to affect half a billion people in the world. T2D is directly associated with obesity and a sedentary lifestyle and is frequently associated with immunosuppression. Immune dysfunction induced by hyperglycemia increases infection frequency and severity. Thus, in developing countries the T2D/TB co-morbidity is frequent and represents one of the most significant challenges for the health-care systems. Several immunoendocrine abnormalities are occurring during the chronic phase of both diseases, such as high extra-adrenal production of active glucocorticoids (GCs) by the activity of 11-β-hydroxysteroid dehydrogenase type 1 (11-βHSD1). 11-βHSD1 catalyzes the conversion of inactive cortisone to active cortisol or corticosterone in lungs and liver, while 11-β-hydroxysteroid dehydrogenase type 2 (11-βHSD2) has the opposite effect. Active GCs have been related to insulin resistance and suppression of Th1 responses, which are deleterious factors in both T2D and TB. The anabolic adrenal hormone dehydroepiandrosterone (DHEA) exerts antagonistic effects on GC signaling in immune cells and metabolic tissues; however, its anabolic effects prohibit its use to treat immunoendocrine diseases. 16α-bromoepiandrosterone (BEA) is a water miscible synthetic sterol related to DHEA that lacks an anabolic effect while amplifying the immune and metabolic properties with important potential therapeutic uses. In this work, we compared the expression of 11-βHSD1 and the therapeutic efficacy of BEA in diabetic mice infected with tuberculosis (TB) (T2D/TB) with respect to non-diabetic TB-infected mice (TB). T2D was induced by feeding mice with a high-fat diet and administering a single low-dose of streptozotocin. After 4 weeks of T2D establishment, mice were infected intratracheally with a high-dose of Mycobacterium tuberculosis strain H37Rv. Then, mice were treated with BEA three times a week by subcutaneous and intratracheal routes. Infection with TB increased the expression of 11-βHSD1 and corticosterone in the lungs and liver of both T2D/TB and TB mice; however, T2D/TB mice developed a more severe lung disease than TB mice. In comparison with untreated animals, BEA decreased GC and 11-βHSD1 expression while increasing 11-βHSD2 expression. These molecular effects of BEA were associated with a reduction in hyperglycemia and liver steatosis, lower lung bacillary loads and pneumonia. These results uphold BEA as a promising effective therapy for the T2D/TB co-morbidity.Fil: López Torres, Manuel Othoniel. Instituto Nacional de la Nutrición Salvador Zubiran; MéxicoFil: Marquina Castillo, Brenda. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Ramos Espinosa, Octavio. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Mata Espinosa, Dulce. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Barrios Payan, Jorge A.. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Baay Guzman, Guillermina. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Huerta Yepez, Sara. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Bini, Estela Isabel. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Torre Villalvazo, Ivan. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Torres, Nimbe. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Tovar, Armando. Instittuto de Ciencias Médicas y Nutrición; MéxicoFil: Chamberlin, William. No especifíca;Fil: Ge, Yu. No especifíca;Fil: Carranza, Maria Andrea. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto Alberto C. Taquini de Investigaciones En Medicina Traslacional. - Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiologicas "prof. Dr. Alberto C. Taquini". Instituto Alberto C. Taquini de Investigaciones En Medicina Traslacional.; ArgentinaFil: Hernández Pando, Rogelio. Instituto Nacional de Ciencias Medicas y Nutricion; Méxic

Maternal overnutrition by hypercaloric diets programs hypothalamic mitochondrial fusion and metabolic dysfunction in rat male offspring

Abstract Background Maternal overnutrition including pre-pregnancy, pregnancy and lactation promotes a lipotoxic insult leading to metabolic dysfunction in offspring. Diet-induced obesity models (DIO) show that changes in hypothalamic mitochondria fusion and fission dynamics modulate metabolic dysfunction. Using three selective diet formula including a High fat diet (HFD), Cafeteria (CAF) and High Sugar Diet (HSD), we hypothesized that maternal diets exposure program leads to selective changes in hypothalamic mitochondria fusion and fission dynamics in male offspring leading to metabolic dysfunction which is exacerbated by a second exposure after weaning. Methods We exposed female Wistar rats to nutritional programming including Chow, HFD, CAF, or HSD for 9 weeks (pre-mating, mating, pregnancy and lactation) or to the same diets to offspring after weaning. We determined body weight, food intake and metabolic parameters in the offspring from 21 to 60 days old. Hypothalamus was dissected at 60 days old to determine mitochondria-ER interaction markers by mRNA expression and western blot and morphology by transmission electron microscopy (TEM). Mitochondrial-ER function was analyzed by confocal microscopy using hypothalamic cell line mHypoA-CLU192. Results Maternal programming by HFD and CAF leads to failure in glucose, leptin and insulin sensitivity and fat accumulation. Additionally, HFD and CAF programming promote mitochondrial fusion by increasing the expression of MFN2 and decreasing DRP1, respectively. Further, TEM analysis confirms that CAF exposure after programing leads to an increase in mitochondria fusion and enhanced mitochondrial-ER interaction, which partially correlates with metabolic dysfunction and fat accumulation in the HFD and CAF groups. Finally, we identified that lipotoxic palmitic acid stimulus in hypothalamic cells increases Ca2+ overload into mitochondria matrix leading to mitochondrial dysfunction. Conclusions We concluded that maternal programming by HFD induces hypothalamic mitochondria fusion, metabolic dysfunction and fat accumulation in male offspring, which is exacerbated by HFD or CAF exposure after weaning, potentially due to mitochondria calcium overflux

Self-reported dietary omega-3 polyunsaturated fatty acids are associated with adipose tissue markers and glucose metabolism in apparently healthy subjects

Background Plasminogen activator inhibitor 1 (PAI-1) and resistin are associated with dysfunctional adipose tissue (AT)-related metabolic complications. The role of dietary eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids in this relationship is unknown. Aim To investigate the association of EPA and DHA with PAI-1 and resistin, as well as the role of this association on the glucose metabolism of apparently healthy subjects. Subjects and methods Thirty-six healthy individuals were included. Validated food frequency questionnaires were used to analyse dietary habits. Inflammatory and glucose metabolism markers were quantified. Subcutaneous AT samples were obtained, and adipocyte number, area, and macrophage content were assessed. Results In 36 subjects aged 56 ± 8 years and with a body mass index of 26 ± 4 kg/m2, logEPA, and logDHA showed significant association with logresistin and a marginal association with PAI-1. Adipocyte number, area, and lognumber of macrophages per adipocyte significantly correlated with PAI-1 but not with logresistin. Although logEPA and logDHA were independently associated with loginsulin, loginsulin resistance, and C-Peptide, the addition of logresistin, but not of PAI-1, into the multivariable model, abolished the associations. Conclusions EPA and DHA could modulate glucose metabolism across AT functional states. Our data indicate that this association is independent of other metabolic risk factors

Genistein stimulates insulin sensitivity through gut microbiota reshaping and skeletal muscle AMPK activation in obese subjects

ObjectiveObesity is associated with metabolic abnormalities, including insulin resistance and dyslipidemias. Previous studies demonstrated that genistein intake modifies the gut microbiota in mice by selectively increasing Akkermansia muciniphila, leading to reduction of metabolic endotoxemia and insulin sensitivity. However, it is not known whether the consumption of genistein in humans with obesity could modify the gut microbiota reducing the metabolic endotoxemia and insulin sensitivity.Research design and methods45 participants with a Homeostatic Model Assessment (HOMA) index greater than 2.5 and body mass indices of ≥30 and≤40 kg/m2 were studied. Patients were randomly distributed to consume (1) placebo treatment or (2) genistein capsules (50 mg/day) for 2 months. Blood samples were taken to evaluate glucose concentration, lipid profile and serum insulin. Insulin resistance was determined by means of the HOMA for insulin resistance (HOMA-IR) index and by an oral glucose tolerance test. After 2 months, the same variables were assessed including a serum metabolomic analysis, gut microbiota, and a skeletal muscle biopsy was obtained to study the gene expression of fatty acid oxidation.ResultsIn the present study, we show that the consumption of genistein for 2 months reduced insulin resistance in subjects with obesity, accompanied by a modification of the gut microbiota taxonomy, particularly by an increase in the Verrucomicrobia phylum. In addition, subjects showed a reduction in metabolic endotoxemia and an increase in 5′-adenosine monophosphate-activated protein kinase phosphorylation and expression of genes involved in fatty acid oxidation in skeletal muscle. As a result, there was an increase in circulating metabolites of β-oxidation and ω-oxidation, acyl-carnitines and ketone bodies.ConclusionsChange in the gut microbiota was accompanied by an improvement in insulin resistance and an increase in skeletal muscle fatty acid oxidation. Therefore, genistein could be used as a part of dietary strategies to control the abnormalities associated with obesity, particularly insulin resistance; however, long-term studies are needed