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Summary: The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2−/−) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2−/− mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis. [ABSTRACT FROM AUTHOR]

Abstract: Telmisartan is an angiotensin II receptor blocker with peroxisome proliferator–activated receptor–γ agonistic properties. Telmisartan prevents weight gain and decreases food intake in models of obesity and in glitazone-treated rodents. This study further investigates the influence of telmisartan and pioglitazone and their association on weight gain and body composition by examining their influence on neuroendocrine mediators involved in food intake. Male C57/Black 6 mice were fed a high-fat diet, weight matched, and randomized in 4 treatment groups: vehicle, pioglitazone, telmisartan, and pioglitazone-telmisartan. Weight gain, food and water intake, body composition, plasma leptin levels, and the hypothalamic expression of neuroendocrine mediators were analyzed. Additional studies were performed with irbesartan and in angiotensin II 1A receptor–knockout mice. Telmisartan abolished weight and fat gain in vehicle- and pioglitazone-treated mice while decreasing food intake, the hypothalamic expression of the agouti-related protein, and plasma leptin levels. Modifications in neuropeptide Y and proopiomelanocortin were not consistent with changes in food intake. The effects on weight gain and expression of the agouti-related protein were intermediate with irbesartan. The effects of telmisartan on weight gain were even more pronounced in angiotensin II 1A receptor–knockout mice. This study confirms the anorexigenic effects of telmisartan in mice fed a high-fat diet and suggests for the first time a functional role of telmisartan on hypothalamic orexigenic agouti-related protein regulation. These anorexigenic properties abolish both weight gain and body composition modifications in fat-fed and glitazone-treated mice. The anorexigenic properties are independent from the angiotensin II 1A receptor. [Copyright &y& Elsevier]

The vagus nerve provides a direct line of communication between the gut and the brain for proper regulation of energy balance and glucose homeostasis. Short-chain fatty acids (SCFAs) produced via gut microbiota fermentation of dietary fiber have been proposed to regulate host metabolism and feeding behavior via the vagus nerve, but the molecular mechanisms have not yet been elucidated. We sought to identify the G-protein-coupled receptors within vagal neurons that mediate the physiological and therapeutic benefits of SCFAs. SCFA, particularly propionate, signaling occurs via free fatty acid receptor 3 (FFAR3), that we found expressed in vagal sensory neurons innervating throughout the gut. The lack of cell-specific animal models has impeded our understanding of gut/brain communication; therefore, we generated a mouse model for cre-recombinase-driven deletion of Ffar3. We comprehensively characterized the feeding behavior of control and vagal-FFAR3 knockout (KO) mice in response to various conditions including fasting/refeeding, western diet (WD) feeding, and propionate supplementation. We also utilized ex vivo organotypic vagal cultures to investigate the signaling pathways downstream of propionate FFAR3 activation. Vagal-FFAR3KO led to increased meal size in males and females, and increased food intake during fasting/refeeding and WD challenges. In addition, the anorectic effect of propionate supplementation was lost in vagal-FFAR3KO mice. Sequencing approaches combining ex vivo and in vivo experiments revealed that the cross-talk of FFAR3 signaling with cholecystokinin (CCK) and leptin receptor pathways leads to alterations in food intake. Altogether, our data demonstrate that FFAR3 expressed in vagal neurons regulates feeding behavior and mediates propionate-induced decrease in food intake. • Lack of vagal FFAR3 increases food intake. • Anorectic effect of propionate is lost when FFAR3 is absent from vagal neurons. • FFAR3 signaling cross-talks with cholecystokinin (CCK) and leptin receptor pathways to alter food intake. [ABSTRACT FROM AUTHOR]

We report a case of a 30-year-old man who presented with advanced heart failure secondary to dilated cardiomyopathy. The patient was diagnosed with limb girdle muscular dystrophy type 2B (LGMD2B), a rare autosomal recessive disease. Cardiomyopathy is only rarely described in dysferlinopathies. This patient is a 30-year old African American male with medical history of left foot crush injury in 2016. The following year after injury he developed progressive exercise intolerance and palpitations. An electrocardiogram (ECG) showed sinus tachycardia. Echocardiogram revealed a severely dilated left ventricle, with increased wall thickness, apical trabeculations and ejection fraction (EF) of 20%. Right ventricle had normal size and function, and there was no significant valvular disease. His functional capacity and cardiac performance on imaging tests did not improve despite guideline directed medical therapy. He also had persistently elevated transaminases. Chronic liver disease workup was negative with liver biopsy showing mild sinusoidal dilatation without significant fibrosis. Persistently elevated transaminases in the absence of liver disease and significant systemic congestion prompted testing for muscle enzymes, which were severely elevated (CK-16,196; Aldolase 84.3 U/l). Neurologic examined revealed mild proximal muscle weakness. Further evaluation included electromyography (EMG), which was consistent with chronic myopathy. Genetic testing revealed a pathogenic splice site variant (c.2643+1GA), and two variants of uncertain significance (p.Asn367Lys, p.Arg553His) in the dysferlin gene. Muscle biopsy was performed which showed active myopathic features with myofiber necrosis and regeneration (Figure 1A, 1B). No chronic remodeling was present. Immunohistochemical staining showed loss of dysferlin expression (figure 1C; insert normal control). Expression of other sarcolemmal proteins like dystrophin was preserved (figure 1D). The biopsy findings support a diagnosis of a dysferlinopathy in the context of the described genetic variants and argue for the combination of the described variants to be disease causing. LGMD2B is a rare limb girdle muscular dystrophy with very few previously reported cases of cardiac muscle involvement. Our case highlights the importance of a comprehensive diagnostic evaluation of idiopathic cardiomyopathy in young patients. Chronically elevated transaminases in young patients should prompt evaluation for myopathy, and genetic evaluation in the appropriate clinical context. [ABSTRACT FROM AUTHOR]