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.

Reprint of: Recent Updates on Obesity Treatments: Available Drugs and Future Directions.

In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlighting the needs to find innovative treatments. Currently, bariatric surgery is the most effective way to efficiently lower body mass. Although great improvements in terms of recovery and patient care were made in these surgical procedures, bariatric surgery remains an option for extreme forms of obesity and seems unable to tackle obesity pandemic expansion. Throughout the last century, numerous pharmacological strategies targeting either peripheral or central components of the energy balance regulatory system were designed to reduce body mass, some of them reaching sufficient levels of efficiency and safety. Nevertheless, obesity drug therapy remains quite limited on its effectiveness to actually overcome the obesogenic environment. Thus, innovative unimolecular polypharmacology strategies, able to simultaneously target multiple actors involved in the obesity initiation and expansion, were developed during the last ten years opening a new promising avenue in the pharmacological management of obesity. In this review, we first describe the clinical features of obesity-associated conditions and then focus on the outcomes of currently approved drug therapies for obesity as well as new ones expecting to reach the clinic in the near future.

Recent Updates on Obesity Treatments: Available Drugs and Future Directions.

In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlighting the needs to find innovative treatments. Currently, bariatric surgery is the most effective way to efficiently lower body mass. Although great improvements in terms of recovery and patient care were made in these surgical procedures, bariatric surgery remains an option for extreme forms of obesity and seems unable to tackle obesity pandemic expansion. Throughout the last century, numerous pharmacological strategies targeting either peripheral or central components of the energy balance regulatory system were designed to reduce body mass, some of them reaching sufficient levels of efficiency and safety. Nevertheless, obesity drug therapy remains quite limited on its effectiveness to actually overcome the obesogenic environment. Thus, innovative unimolecular polypharmacology strategies, able to simultaneously target multiple actors involved in the obesity initiation and expansion, were developed during the last ten years opening a new promising avenue in the pharmacological management of obesity. In this review, we first describe the clinical features of obesity-associated conditions and then focus on the outcomes of currently approved drug therapies for obesity as well as new ones expecting to reach the clinic in the near future.

Oral Pharmacological Activation of Hypothalamic Guanylate Cyclase 2C Receptor Stimulates Brown Fat Thermogenesis to Reduce Body Weight.

Linaclotide is a synthetic peptide approved by the FDA for the treatment of constipation-predominant irritable bowel syndrome and chronic constipation. Linaclotide binds and activates the transmembrane receptor guanylate cyclase 2C (Gucy2c). Uroguanylin (UGN) is a 16 amino acid peptide that is mainly secreted by enterochromaffin cells in the duodenum and proximal small intestine. UGN is the endogenous ligand of Gucy2c and decreases body weight in diet-induced obese (DIO) mice via the activation of the thermogenic program in brown adipose tissue. Therefore, we wanted to evaluate whether oral linaclotide could also improve DIO mice metabolic phenotype. In this study, we have demonstrated that DIO mice orally treated with linaclotide exhibited a significant reduction of body weight without modifying food intake. Linaclotide exerts its actions through the central nervous system, and more specifically, via Gucy2c receptors located in the mediobasal hypothalamus, leading to the activation of the sympathetic nervous system to trigger the thermogenic activity of brown fat stimulating energy expenditure. These findings indicate for first time that, in addition to its effects at intestinal level to treat irritable bowel syndrome with constipation and chronic constipation, linaclotide also exerts a beneficial effect in whole body metabolism.

Genetic Targeting of GRP78 in the VMH Improves Obesity Independently of Food Intake.

Recent data have demonstrated that the hypothalamic GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates brown adipose tissue (BAT) thermogenesis by acting downstream on AMP-activated protein kinase (AMPK). Herein, we aimed to investigate whether genetic over-expression of GRP78 in the ventromedial nucleus of the hypothalamus (VMH: a key site regulating thermogenesis) could ameliorate very high fat diet (vHFD)-induced obesity. Our data showed that stereotaxic treatment with adenoviruses harboring GRP78 in the VMH reduced hypothalamic endoplasmic reticulum ER stress and reversed vHFD-induced obesity. Herein, we also demonstrated that this body weight decrease was more likely associated with an increased BAT thermogenesis and browning of white adipose tissue (WAT) than to anorexia. Overall, these results indicate that the modulation of GRP78 in the VMH may be a target against obesity.

Microparticles from apoptotic RAW 264.7 macrophage cells carry tumour necrosis factor-α functionally active on cardiomyocytes from adult mice.

After ischaemic injury and in patients with atherosclerosis, the pool of inflammatory macrophages is enlarged in the heart and in atherosclerotic plaques. Monocyte/macrophage-derived microparticles (MPs) are part of the pathological process of unstable atherosclerotic plaques. The present study focused on effects of MPs, produced by apoptotic murine RAW 264.7 macrophage cell line, in adult murine cardiomyocytes. Flow cytometry and western blot analysis showed that these MPs contained the soluble form of tumour necrosis factor alpha (TNF-α). Cardiomyocyte sarcomere shortening amplitudes and kinetics were reduced within 5 min of exposure to these MPs. Conversely, Ca(2+) transient amplitude and kinetics were not modified. The contractile effects of MPs were completely prevented after pretreatment with nitric oxide synthase, guanylate cyclase or TNF-α inhibitors as well as blocking TNF-α receptor 1 with neutralizing antibody. Microscopy showed that, after 1 h, MPs were clearly surrounding rod-shaped cardiomyocytes, and after 2 h they were internalized into cardiomyocytes undergoing apoptosis. After 4 h of treatment with MPs, cardiomyocytes expressed increased caspase-3, caspase-8, Bax and cytochrome C. Thus, MPs from apoptotic macrophages induced a negative inotropic effect and slowing of both contraction and relaxation, similar to that observed in the presence of TNF-α. The use of specific inhibitors strongly suggests that TNF-α receptors and the guanylate cyclase/cGMP/PKG pathway were involved in the functional responses to these MPs and that the mitochondrial intrinsic pathway was implicated in their proapoptotic effects. These data suggest that MPs issued from activated macrophages carrying TNF-α could contribute to propagation of inflammatory signals leading to myocardial infarction.