Differential Effects of Bariatric Surgery and Caloric Restriction on Hepatic One-Carbon and Fatty Acid Metabolism

Weight loss interventions, including dietary changes, pharmacotherapy, or bariatric surgery, prevent many of the adverse consequences of obesity, and may also confer intervention-specific benefits beyond those seen with decreased weight alone. We compared the molecular effects of different interventions on liver metabolism to understand the mechanisms underlying these benefits. Male rats on a high-fat, high-sucrose diet underwent sleeve gastrectomy (SG) or intermittent fasting with caloric restriction (IF-CR), achieving equivalent weight loss. The interventions were compared t

Mapping the Metabolic Reprogramming Induced by Sodium-Glucose Cotransporter 2 Inhibition

Diabetes is associated with increased risk for kidney disease, heart failure, and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent these adverse outcomes; however, the mechanisms involved are not clear. We generated a roadmap of the metabolic alterations that occur in different organs in diabetes and in response to SGLT2i. In vivo metabolic labeling with 13C-glucose in normoglycemic and diabetic mice treated with or without dapagliflozin, followed by metabolomics and metabolic flux analyses, showed that, in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis. SGLT2 inhibition increased glucose oxidation in all organs; in the kidney, this was associated with modulation of the redox state. Diabetes was associated with altered methionine cycle metabolism, evident by decreased betaine and methionine levels, whereas treatment with SGLT2i increased hepatic betaine along with decreased homocysteine levels. mTORC1 activity was inhibited by SGLT2i along with stimulation of AMPK in both normoglycemic and diabetic animals, possibly explaining the protective effects against kidney, liver, and heart diseases. Collectively, our findings suggest that SGLT2i induces metabolic reprogramming orchestrated by AMPK-mTORC1 signaling with common and distinct effects in various tissues, with implications for diabetes and aging

Diasporic Security and Jewish Identity

This paper explores the relationship between identity and security through an investigation into Jewish diasporic identity. The paper argues that the convention of treating identity as an objective referent of security is problematic, as the Jewish diaspora experience demonstrates. The paper presents a new way of conceptualizing identity and security by introducing the concept of diasporic security. Diasporic security reflects the geographical experience of being a member of a trans-state community, of having a fluid identity that is shaped by sometimes contradictory discourses emanating from a community that resides both at home and abroad. In introducing the concept of diasporic security, the paper makes use of literature in Diaspora Studies, Security Studies, recent works in contemporary political theory and sociology, and Woody Allen's film, Deconstructing Harry (1997)

The Obesogenic and Glycemic Effect of Bariatric Surgery in a Family with a Melanocortin 4 Receptor Loss-of-Function Mutation

We report the long-term response to bariatric surgery in a singular family of four adolescents with severe obesity (41–82 kg/m2), homozygous for the C271R loss-of-function mutation in the melanocortin 4 receptor (MC4R), and three adults heterozygous for the same mutation. All patients had similar sociodemographic backgrounds and were followed for an average of 7 years. Three of the four homozygous patients regained their full weight (42–77 kg/m2), while the fourth lost weight but remained obese with a body mass index of 60 kg/m2. Weight regain was associated with relapse of most comorbidities, yet hyperglycemia did not relapse or was delayed. A1c levels were reduced in homozygous and heterozygous patients. The long-term follow-up data on this very unique genetic setting show that weight loss and amelioration of obesity following bariatric surgery require active MC4R signaling, while the improvement in glycemia is in part independent of weight loss. The study validates animal models and demonstrates the importance of biological signaling in the regulation of weight, even after bariatric surgery

Cardiac leptin overexpression in the context of acute MI and reperfusion potentiates myocardial remodeling and left ventricular dysfunction.

BACKGROUND:Acute MI induces leptin expression in the heart, however the role of myocardial leptin in cardiac ischemia and reperfusion (IR) remains unknown. To shed light on the effects of elevated levels of leptin in the myocardium, we overexpressed cardiac leptin and assessed local remodeling and myocardial function in this context. METHODS AND RESULTS:Cardiac leptin overexpression was stimulated in mice undergoing IR by a single intraperitoneal injection of leptin antagonist (LepA). All mice exhibited a normal pattern of body weight gain. A rapid, long-term upregulation of leptin mRNA was demonstrated in the heart, adipose, and liver tissues in IR/LepA-treated mice. Overexpressed cardiac leptin mRNA extended beyond postoperative day (POD) 30. Plasma leptin peaked 7.5 hours postoperatively, especially in IR/LepA-treated mice, subsiding to normal levels by 24 hours. On POD-30 IR/LepA-treated mice demonstrated cardiomyocyte hypertrophy and perivascular fibrosis compared to IR/saline controls. Echocardiography on POD-30 demonstrated eccentric hypertrophy and systolic dysfunction in IR/LepA. We recorded reductions in Ejection Fraction (p<0.001), Fraction Shortening (p<0.01), and Endocardial Fraction Area Change (p<0.01), and an increase in Endocardial Area Change (p<0.01). Myocardial remodeling in the context of IR and cardiac leptin overexpression was associated with increased cardiac TGFβ ligand expression, activated Smad2, and downregulation of STAT3 activity. CONCLUSIONS:Cardiac IR coinciding with increased myocardial leptin synthesis promotes cardiomyocyte hypertrophy and fibrosis and potentiates myocardial dysfunction. Plasma leptin levels do not reflect cardiac leptin synthesis, and may not predict leptin-related cardiovascular morbidity. Targeting cardiac leptin is a potential treatment for cardiac IR damage

Additional file 1: of ADMP controls the size of Spemann's organizer through a network of self-regulating expansion-restriction signals

Mathematical model. Mathematical model, parameter description and parameter values. (PDF 94 kb

Additional file 2: Figure S1. of ADMP controls the size of Spemann's organizer through a network of self-regulating expansion-restriction signals

Robustness and sensitivity of the size of the organizer induction domain to receptor distribution. (A) Relative organizer induction domain size as a function of ventralization or dorsalization of ALK1 and ALK2 expression at time t = 1 h, compared to the reference parameter set. ALK1 and ALK2 expression pattern is given by a Hill function. org defines the position along the dorsal-ventral axis where ALK1 and ALK2 reach half their induction. Dotted line (blue) denotes the relative organizer size in the reference data set, here, set to 1, which is obtained when org equals 500 μm (black tick). The relative organizer size is sensitive to the Alk1, Alk2 expression pattern as defined by org (400–600 μm). Ventralization of ALK1 and ALK2 expression pattern (org < 500) leads to an increase in the organizer induction domain, while dorsalization (org > 500) leads to a decrease in organizer size. (B) ALK1 (red) and ALK2 (blue) profiles for a ventralized parameter (org = 450 μm). Dotted line shows the position along the dorsoventral axis (org) where ALK1 and ALK2 reach half their maximal induction. Black tick marks the dorsoventral midline and the position of org in the reference parameter set. Each tick in the X axis marks 50 μm. (C) Size of the organizer induction domain in the ventralized parameter set as a function of ADMP flux. Y axis is the relative size of the organizer induction domain as in A. ADMP flux in reference parameter set is 1 μmnM s–1. (D) Profiles (ALK1 (red) and ALK2 (blue)) for a dorsalized parameter set (org = 550 μm). The dorsoventral position where ALK1 and ALK2 reach half their maximal induction, corresponding to org, is shown (dotted line). (E) Size of the organizer induction domain size in the dorsalized parameter set as a function of ADMP flux as in C. (PDF 240 kb