Sebastian M. Schmid

Circadian desynchrony promotes metabolic disruption in a mouse model of shiftwork.

Shiftwork is associated with adverse metabolic pathophysiology, and the rising incidence of shiftwork in modern societies is thought to contribute to the worldwide increase in obesity and metabolic syndrome. The underlying mechanisms are largely unknown, but may involve direct physiological effects of nocturnal light exposure, or indirect consequences of perturbed endogenous circadian clocks. This study employs a two-week paradigm in mice to model the early molecular and physiological effects of shiftwork. Two weeks of timed sleep restriction has moderate effects on diurnal activity patterns, feeding behavior, and clock gene regulation in the circadian pacemaker of the suprachiasmatic nucleus. In contrast, microarray analyses reveal global disruption of diurnal liver transcriptome rhythms, enriched for pathways involved in glucose and lipid metabolism and correlating with first indications of altered metabolism. Although altered food timing itself is not sufficient to provoke these effects, stabilizing peripheral clocks by timed food access can restore molecular rhythms and metabolic function under sleep restriction conditions. This study suggests that peripheral circadian desynchrony marks an early event in the metabolic disruption associated with chronic shiftwork. Thus, strengthening the peripheral circadian system by minimizing food intake during night shifts may counteract the adverse physiological consequences frequently observed in human shift workers.

Early morning rise in hypothalamic-pituitary-adrenal activity: a role for maintaining the brain's energy balance.

A profound rise in secretory activity in the early morning hours hallmarks the circadian regulation of the hypothalamic-pituitary-adrenal (HPA) stress axis. Functions and mechanisms underlying this regulation are barely understood. We tested the hypothesis that the early morning rise in HPA axis activity originates in part from a negative energy balance due to nocturnal fasting and concomitant increases in cerebral glucose demands. According to a 2x2 design, healthy men were infused with glucose (4.5mg/kgmin, 2300-0700h) and saline, respectively, during nocturnal sleep (n=9) or wakefulness (n=11). Circulating concentrations of ACTH, cortisol, glucose, insulin, and leptin were measured and food consumption in the next morning was assessed. Independent of sleep, glucose infusion reduced levels of ACTH (P<0.01) and cortisol (P<0.02) during the second night half. In the Sleep group, glucose infusion enhanced rapid eye movement (REM) sleep at the expense of sleep stage 2 (each P<0.05). Glucose infusion increased leptin levels in both groups (P<0.005) and reduced morning food intake in the Wake (P<0.02) but not in the Sleep group (P>0.46). Our findings support the view that increasing energy demands of the brain towards the end of the night essentially contribute to the early morning rise in HPA axis activity. Sleep is not critically involved in this glucose-glucocorticoid feedback loop but may reduce the brains sensitivity to the anorexigenic effect of enhanced glucose supply.

Mitochondrial gene polymorphisms alter hepatic cellular energy metabolism and aggravate diet-induced non-alcoholic steatohepatitis

Objective Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH). However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH. Methods To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mtFVB/N mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T) of the mitochondrial ATP synthase protein 8 (mt-ATP8). Results At baseline conditions, C57BL/6J-mtFVB/N mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS). Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mtFVB/N mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells. Conclusions We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial dysfunction. However, a second hit, such as dietary stress, was required to cause hepatic steatosis and inflammation. This study suggests a causative role of hepatic mitochondrial dysfunction in the development of experimental NASH.

Comparison of fatty acid composition of plasma lipid fractions in well-nourished Nigerian and German infants and toddlers

The dietary intake of essential fatty acids is reflected by the plasma lipid composition. Only scanty data is available on the pattern of plasma fatty acids in young children and the influence of different environments. We analyzed the fatty acid composition of plasma sterolesters, triglycerides, and phospholipids in well-nourished-appearing children from Benin City, Nigeria (n = 8; aged 14.1 ± 7.2 months) and Düsseldorf, FRG (n = 17; aged 15.2 ± 5.1 months). The Nigerian group tended to have bigger proportions of the essential -6-fatty acids, linoleic acid, and its metabolites, and by far higher values for long-chain co-3-fatty acids, which are considered to be protective against atherogenesis. The saturated and nonessential monoenoic fatty acids tended to be lower in the Nigerian children, and the ratio of polyun-saturated to saturated fatty acids was higher. We conclude that the quality of dietary fat in the German children was worse and may imply an increased risk for development of atherosclerosis.

Impact of nutrition on social decision making

Significance Food intake is essential for survival in all species for meeting energetic demands. However, food intake also modulates various biochemical processes underlying cognition. Across two studies, we showed that different macronutrient compositions in standard European meals affect plasma neurotransmitter precursor levels, and these in turn influence social decision making. Our results provide evidence that variations in the macronutrient content of a normal European meal exert a significant impact on high-level human cognition. This study opens perspectives on nutrition-driven cognition modulation. The results have implications for education, economics, and public policy by emphasizing the importance of a balanced diet on fundamental expressions of cognition. Food intake is essential for maintaining homeostasis, which is necessary for survival in all species. However, food intake also impacts multiple biochemical processes that influence our behavior. Here, we investigate the causal relationship between macronutrient composition, its bodily biochemical impact, and a modulation of human social decision making. Across two studies, we show that breakfasts with different macronutrient compositions modulated human social behavior. Breakfasts with a high-carbohydrate/protein ratio increased social punishment behavior in response to norm violations compared with that in response to a low carbohydrate/protein meal. We show that these macronutrient-induced behavioral changes in social decision making are causally related to a lowering of plasma tyrosine levels. The findings indicate that, in a limited sense, “we are what we eat” and provide a perspective on a nutrition-driven modulation of cognition. The findings have implications for education, economics, and public policy, and emphasize that the importance of a balanced diet may extend beyond the mere physical benefits of adequate nutrition.

Konservative Therapie der Adipositas

ZusammenfassungHintergrundDie Prävalenz der Adipositas ist in den letzten Jahren stetig angestiegen. Adipositas stellt als chronische Krankheit weltweit ein Gesundheitsproblem dar und ist mit einer Vielzahl von Komorbiditäten wie beispielsweise Typxa02 Diabetes mellitus assoziiert.Ziel der ArbeitDie vorliegende Arbeit gibt eine Übersicht über die Möglichkeiten und Grenzen der konservativen Therapie bei Adipositas. Zudem werden die Ursachen für die Adipositasentwicklung und die Assoziation von Adipositas und schlafbezogenen Atmungsstörungen (SBAS) erläutert.Material und MethodenEs wurde Literatur zusammengefasst, die sich der konservativen Adipositastherapie in Form von Ernährungs‑, Bewegungs- und Verhaltenstherapie sowie medikamentöser Therapie widmet. Zudem wurde eine Vielzahl von experimentellen Studien zitiert, welche Grundlagenwissen in diesem Themenbereich liefern.Ergebnisse und DiskussionAufgrund der Komplexität der Pathogenese der Adipositas muss konservative Adipositastherapie auf einem multifaktoriellen Ansatz bestehen. Die Grundbausteine sind eine Ernährungs‑, Bewegungs- und Verhaltenstherapie. Bei nicht ausreichender Gewichtsreduktion kann eine zusätzliche medikamentöse Therapie indiziert sein.AbstractBackgroundObesity as axa0chronic disease leads to several adverse metabolic comorbidities like typexa02 diabetes mellitus and its prevalence has increased continuously over the last decades.ObjectivesThe aim of this work is to present an overview of the possibilities and limitations of non-surgical therapy for patients with obesity. Furthermore, it explains the development of obesity as well as the association between sleep-related breathing disorders and obesity.Materials and methodsLiterature and guidelines focusing on non-surgical therapy of obesity, i.u202fe. diet, physical activity and behavior, were screened. Furthermore, data on several experimental studies regarding the weight-lowering effects of drugs were included.Results and discussionDue to the complexity of the pathogeneses of obesity, the therapy should base on axa0multifactorial approach, consisting of nutritional and physical activity counselling and behavioral therapy. If this “basic” program is not effective the use of weight-lowering drugs could be considered.

Resting energy expenditure after Roux-en Y gastric bypass surgery

BACKGROUNDnThe mechanisms by which Roux-en Y gastric bypass surgery (RYGB) provokes weight loss are incompletely understood. Enhanced energy expenditure may be one contributing mechanism. Previous results on changes in resting energy expenditure (REE) after RYGB are inconsistent.nnnOBJECTIVESnThe aim of the present study was to assess changes in REE after RYGB and whether REE predicts weight loss (percentage weight loss).nnnSETTINGnObesity Clinic.nnnMETHODSnREE was measured by indirect calorimetry (mREE) before and 1 year after RYGB in 233 patients with severe obesity (175 women; all body mass index ≥35.0 kg·m-2) and mREE was compared with predicted REE (pREE) and expressed as percentage of pREE (%pREE). For calculation of pREE, 2 new equations were developed from an independent reference group of overweight and obese patients (852 patients; body mass index range: 27.4-73.0 kg·m-2) that were examined in exactly the same setting as the bariatric patients that were followed-up after RYGB. The new equations were based on either anthropometric (pREE-BM, %pREE-BM) or body composition (pREE-BC; %pREE-BC) parameters.nnnRESULTSnAfter RYGB, absolute mREE was reduced by 20.4 ± 11.0% (-458 ± 277 kcal·d-1; P<.001). Compared with pREE-BM (post-%REE-BM) and pREE-BC (post-%REE-BC), mREE was 2.3 ± 9.4% and 1.6 ± 9.5%, respectively, higher (both P ≤ .03). Post-%pREE-BM and post- %pREE-BC after RYGB were positively correlated with percentage weight loss (r = .206 and r = .231; both P ≤ .003).nnnCONCLUSIONSnData indicate a slightly higher mREE than pREE after RYGB. Although the underlying mechanisms of this observation remain to be elucidated our finding may play a role for weight loss outcomes after the surgery.

Reply to Raison and Raichlen: Why does nutrition impact social decision making?

In our PNAS article (1), we show how the macronutrient composition of a meal can impact social decision making. Specifically, with a greater protein intake, participants plasma tyrosine levels were elevated, which resulted in a more tolerant participants’ response toward unfair offers. In other words, with a greater carbohydrate intake, participants’ responses were more sensitive to unfairness. In their letter, Raison and Raichlen (2) suggest an overarching evolutionary perspective on and inspiring interpretation of our previously published data (1) on social decision making in the context of nutritional composition. We very much welcome this important question on the profound sense of an evolutionary mechanism … nn[↵][1]1To whom correspondence should be addressed. Email: soyoung.q.park{at}gmail.com.nn [1]: #xref-corresp-1-1

Cardiorespiratory Fitness is Associated with Glycated Hemoglobin and Triglyceride Levels in Severely Obese Men: A Retrospective Clinical Data Analysis

BACKGROUNDnEven subjects with severe obesity show a wide range of metabolic health states, with some showing marked alterations in glucose and lipid metabolism whereas others do not. In severely obese women, we could recently show that the degree of cardiorespiratory fitness is, independently of body mass and age, associated with several markers of glucose and lipid metabolism.nnnAIMSnIn our retrospective study on a clinical data set, we questioned whether such an association also exists in severely obese men.nnnMETHODSnCardiorespiratory fitness, i.u2009e. workload (Wpeak) and oxygen uptake (V̇O2,peak) at peak exercise, was assessed by a bicycle spiroergometry in 133 severely obese men (all BMI>35u2009kg m-2). The following metabolic blood markers were also measured: Fasting serum glucose, insulin, triglycerides (TG), total, low-, high-density cholesterol (Chol, LDL, HDL), uric acid, and whole blood glycated hemoglobin (HbA1c). The Chol/HDL ratio and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were also calculated.nnnRESULTSnMultiple stepwise linear regression models including age, body mass, and smoking status as independent variables revealed that Wpeak and V̇O2,peak, explained 4.5 to 10.7% of variance in HbA1c and TG (all beta<-u20090.22; all p<0.02). Including fat free mass instead of body mass in respective models revealed that both Wpeak and V̇O2,peak were predictors of HbA1c and TG (all beta<-u20090.265; all p<0.013), respectively, while Wpeak also accounted for variance in glucose and Chol (both beta<-u20090.259; both p<0.023).nnnCONCLUSIONSnSimilar to previous observations in women, our data indicate that cardiorespiratory fitness assessed by bicycle ergospirometry test is associated with glucose and lipid metabolism in severely obese men. The strength of the found associations suggest a mild to moderate influence of cardiorespiratory fitness on metabolic health in severe obesity.

Coupling the circadian clock to homeostasis: the role of Period in timing physiology

A plethora of physiological processes show stable and synchronized daily oscillations that are either driven or modulated by biological clocks. A circadian pacemaker located in the suprachiasmatic nucleus of the ventral hypothalamus coordinates 24-hour oscillations of central and peripheral physiology with the environment. The circadian clockwork involved in driving rhythmic physiology is composed of various clock genes that are interlocked via a complex feedback loop to generate precise yet plastic oscillations of ∼24 hours. This review focuses on the specific role of the core clockwork gene Period1 and its paralogs on intra-oscillator and extra-oscillator functions, including, but not limited to, hippocampus-dependent processes, cardiovascular function, appetite control, as well as glucose and lipid homeostasis. Alterations in Period gene function have been implicated in a wide range of physical and mental disorders. At the same time, a variety of conditions including metabolic disorders also impact clock gene expression, resulting in circadian disruptions, which in turn often exacerbates the disease state.