Ketogenic Diet and Weight Loss: Is There an Effect on Energy Expenditure?

A dysregulation between energy intake (EI) and energy expenditure (EE), the two components of the energy balance equation, is one of the mechanisms responsible for the development of obesity. Conservation of energy equilibrium is deemed a dynamic process and alterations of one component (energy intake or energy expenditure) lead to biological and/or behavioral compensatory changes in the counterpart. The interplay between energy demand and caloric intake appears designed to guarantee an adequate fuel supply in variable life contexts. In the past decades, researchers focused their attention on finding efficient strategies to fight the obesity pandemic. The ketogenic or "keto" diet (KD) gained substantial consideration as a potential weight-loss strategy, whereby the concentration of blood ketones (acetoacetate, 3-beta-hydroxybutyrate, and acetone) increases as a result of increased fatty acid breakdown and the activity of ketogenic enzymes. It has been hypothesized that during the first phase of KDs when glucose utilization is still prevalent, an increase in EE may occur, due to increased hepatic oxygen consumption for gluconeogenesis and for triglyceride-fatty acid recycling. Later, a decrease in 24-h EE may ensue due to the slowing of gluconeogenesis and increase in fatty acid oxidation, with a reduction of the respiratory quotient and possibly the direct action of additional hormonal signals

Phenotypic effects of an induced mutation of the ObRa isoform of the leptin receptor

Leptin receptors play critical roles in mediating leptin's pleiotropic effects on mammalian physiology. To date, six splice variants of the leptin receptor gene have been identified . These splice variants have identical extracellular leptin binding motifs but different intracellular C termini. The finding that mutations specifically ablating the function of ObRb cause obesity has established a critical role for this isoform in leptin signaling . ObRa is the most abundant splicing isoform with a broad tissue distribution [5], and it has been proposed to play roles in regulating leptin bioavailability, CSF (cerebrospinal fluid) transport and function by forming heterodimers with ObRb and also activating signal transduction via JAK2 in-vitro . To assess the in-vivo role of ObRa, we generated an ObRa KO mouse by deleting the ObRa-specific exon 19a. Homozygous mutant mice breed normally and are indistinguishable from wild-type mice on regular chow diet, but show a slightly increased basal plasma leptin, a slight improvement of their GTT and a slightly reduced response to systemic leptin administration. These mice also show a modest but statistically significant increase in weight when placed on a high fat diet with a slightly reduced CSF/plasma ratio of leptin. These data suggest that ObRa plays a role in mediating some of leptin's effects but that the phenotypic consequences are modest compared to a deletion of ObRb

Ophthalmologic evaluation of severely obese patients undergoing bariatric surgery: A pilot, monocentric, prospective, open-label study

PURPOSE: The aim of this study was to investigate the pathogenic role of obesity on blinding eye diseases in a population of severely obese patients with no history of eye diseases, and to verify whether weight loss induced by bariatric surgery may have a protective effect. METHODS: This was a pilot, monocentric, prospective, and open label study conducted at the University Hospital of Pisa. Fifty-seven severely obese patients with a mean body mass index value of 44.1 ± 6 kg/m2 were consecutively recruited and received a complete ophthalmological evaluation and optical coherence tomography. Twenty-nine patients who underwent gastric bypass were evaluated also 3 months, and 1 year after surgery. RESULTS: At baseline, blood pressure value were directly and significantly related to intraocular pressure values (p<0.05, R = 0.35). Blood pressure values were also significantly and inversely related to retinal nerve fiber layer thickness, particularly in the temporal sector (RE p<0.05 r-0.30; LE p<0.01, R = -0.43). Moreover, minimum foveal thickness values were significantly and inversely associated with body mass index (RE p<0.02, R = -0.40; LE p<0.02, R = -0.30). A significant reduction of body mass index (p<0.05) and a significant (p<0.05) improvement of blood pressure was observed three months and one year after gastric bypass, which were significantly associated with an increase in retinal nerve fiber layer thickness and minimum foveal thickness values in both eyes (p<0.05). CONCLUSIONS: The results of this study suggest that obese patients may have a greater susceptibility to develop glaucomatous optic nerve head damage and age-related macular degeneration. Moreover, weight reduction and improvement of comorbidities obtained by bariatric surgery may be effective in preventing eye disease development by improving retinal nerve fiber layer and foveal thickness

Liver enlargement predicts obstructive sleep apnea–hypopnea syndrome in morbidly obese women

Obstructive sleep apnea–hypopnea syndrome (OSAHS) is frequently present in patients with severe obesity, but its prevalence especially in women is not well defined. OSAHS and non-alcoholic fatty liver disease are common conditions, frequently associated in patients with central obesity and metabolic syndrome and are both the result of the accumulation of ectopic fat mass. Identifying predictors of risk of OSAHS may be useful to select the subjects requiring instrumental sleep evaluation. In this cross-sectional study, we have investigated the potential role of hepatic left lobe volume (HLLV) in predicting the presence of OSAHS. OSAHS was quantified by the apnea/hypopnea index (AHI) and oxygen desaturation index in a cardiorespiratory inpatient sleep study of 97 obese women [age: 47 ± 11 years body mass index (BMI): 50 ± 8 kg/m2]. OSAHS was diagnosed when AHI was ≥5. HLLV, subcutaneous and intra-abdominal fat were measured by ultrasound. After adjustment for age and BMI, both HLLV and neck circumference (NC) were independent predictors of AHI. OSAHS was found in 72% of patients; HLLV ≥ 370 cm3 was a predictor of OSAHS with a sensitivity of 66%, a specificity of 70%, a positive and negative predictive values of 85 and 44%, respectively (AUC = 0.67, p < 0.005). A multivariate logistic model was used including age, BMI, NC, and HLLV (the only independent predictors of AHI in a multiple linear regression analyses), and a cut off value for the predicted probability of OSAHS equal to 0.7 provided the best diagnostic results (AUC = 0.79, p < 0.005) in terms of sensitivity (76%), specificity (89%), negative and positive predictive values (59 and 95%, respectively). All patients with severe OSAHS were identified by this prediction model. In conclusion, HLLV, an established index of visceral adiposity, represents an anthropometric parameter closely associated with OSAHS in severely obese women

The antidepressant fluoxetine acts on energy balance and leptin sensitivity via BDNF

Leptin and Brain Derived Neurotrophic Factor (BDNF) pathways are critical players in body weight homeostasis. Noninvasive treatments like environmental stimulation are able to increase response to leptin and induce BDNF expression in the brain. Emerging evidences point to the antidepressant selective serotonin reuptake inhibitor Fluoxetine (FLX) as a drug with effects similar to environmental stimulation. FLX is known to impact on body weight, with mechanisms yet to be elucidated. We herein asked whether FLX affects energy balance, the leptin system and BDNF function. Adult lean male mice chronically treated with FLX showed reduced weight gain, higher energy expenditure, increased sensitivity to acute leptin, increased hypothalamic BDNF expression, associated to changes in white adipose tissue expression typical of "brownization". In the Ntrk2tm1Ddg/J model, carrying a mutation in the BDNF receptor Tyrosine kinase B (TrkB), these effects are partially or totally reversed. Wild type obese mice treated with FLX showed reduced weight gain, increased energy output, and differently from untreated obese mice, a preserved acute response to leptin in terms of activation of the intracellular leptin transducer STAT3. In conclusion, FLX impacts on energy balance and induces leptin sensitivity and an intact TrkB function is required for these effects to take place

Immunological features of patients affected by Barraquer-Simons syndrome

Background: C3 hypocomplementemia and the presence of C3 nephritic factor (C3NeF), an autoantibody causing complement system over-activation, are common features among most patients affected by Barraquer-Simons syndrome (BSS), an acquired form of partial lipodystrophy. Moreover, BSS is frequently associated with autoimmune diseases. However, the relationship between complement system dysregulation and BSS remains to be fully elucidated. The aim of this study was to provide a comprehensive immunological analysis of the complement system status, autoantibody signatures and HLA profile in BSS. Thirteen subjects with BSS were recruited for the study. The circulating levels of complement components, C3, C4, Factor B (FB) and Properdin (P), as well as an extended autoantibody profile including autoantibodies targeting complement components and regulators were assessed in serum. Additionally, HLA genotyping was carried out using DNA extracted from peripheral blood mononuclear cells. Results: C3, C4 and FB levels were significantly reduced in patients with BSS as compared with healthy subjects. C3NeF was the most frequently found autoantibody (69.2% of cases), followed by anti-C3 (38.5%), and anti-P and anti- FB (30.8% each). Clinical data showed high prevalence of autoimmune diseases (38.5%), the majority of patients (61.5%) being positive for at least one of the autoantibodies tested. The HLA allele DRB1*11 was present in 54% of BSS patients, and the majority of them (31%) were positive for *11:03 (vs 1.3% allelic frequency in the general population). Conclusions: Our results confirmed the association between BSS, autoimmunity and C3 hypocomplementemia. Moreover, the finding of autoantibodies targeting complement system proteins points to complement dysregulation as a central pathological event in the development of BSS.This work was supported by Instituto de Salud Carlos III (Ministerio de Ciencia, Innovación y Universidades, Gobierno de España) and Fondos FEDER (PI15–00255 to M.L-T. and PI08–1449 to D.A-V.), Complemento II-CM network (B2017/BMD3673 to M.L-T), the intramural research program of the Xunta de Galicia (Programa de Consolidación e Estructuración de Unidades de Investigación Competitivas, grant ED341b 2017/19 to D.A-V.), the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP) (to D.A-V., to F.C. and to P.N.

Morphologies

Séminaire commun avec la participation de : Olivier Abel, Luciano Boi, Jean-Claude Bonne, Marion Carel, Giovanni Careri, Enrico Castelli Gattinara, Patrice Ceccarini, Danièle Cohn, Georges Didi-Huberman, Fernando Gil, Maurizio Gribaudi, Ryozo Hiyama, Bernard Jaulin, Gérard Jorland, Farhad Khosrokhavar, Hervé Le Bras, Giovanni Levi, Sabina Loriga, Silvia Mancini, Jean Petitot, Pierre Rosenstiehl, Carlo Severi, Wiktor Stoczkowski, Lorraine Verner Compte rendu non communiqué

Morphologies

Séminaire commun avec la participation de : Olivier Abel, Luciano Boi, Jean-Claude Bonne, Marion Carel, Giovanni Careri, Enrico Castelli Gattinara, Patrice Ceccarini, Ryozo Hiyama, Georges Didi-Huberman, Maurizio Gribaudi, Bernard Jaulin, Gérard Jorland, Farhad Khosrokhavar, Hervé Le Bras, Giovanni Levi, Sabina Loriga, Silvia Mancini, Zacarías Moutoukias, Jean Petitot, Pierre Rosenstiehl, Carlo Severi, Irène Tamba, Lorraine Verner, Wiktor Stoczkowski Compte rendu non communiqué

Morphologies

Séminaire commun avec la participation d’Olivier Abel, Luciano Boi, Jean-Claude Bonne, Marion Carel, Giovanni Careri, Enrico Castelli Gattinara, Patrice Ceccarini, Danièle Cohn, Ryozo Hiyama, Georges Didi-Huberman, Fernando Gil, Maurizio Gribaudi, Bernard Jaulin, Farhad Khosrokhavar, Hervé Le Bras, Giovanni Levi, Sabina Loriga, Silvia Mancini, Zacarias Moutoukias, Jean Petitot, Pierre Rosenstiehl, Carlo Severi, Lorraine Verner, Wiktor Stoczkowski Voici, les différents sujets abordés et discut..

European lipodystrophy registry: background and structure

Abstract: Background: Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. Results: The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. Conclusions: A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. Study registration: ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered