Sleep disorders in a naturalistic cohort of Dutch psychiatric outpatients: prevalence rates and associations with psychopathology symptom severity and well-being.

Sleep problems are very common in individuals with a mental disorder. Given the abundant evidence indicating the negative impact of disturbed sleep on mental health outcome, insight into the prevalence of all types of sleep disorders in specific mental disorders and neurodevelopmental conditions is of practical importance. Therefore, we estimated the prevalence of six types of sleep disorders with the Holland Sleep Disorders Questionnaire in an overall mental health sample (n = 1082) and separately for different mental and neurodevelopmental conditions. Furthermore, associations between specific sleep disorders, psychopathology and well-being were studied. The impact of the total number of sleep disorders on these associations was examined. Overall, 46.2% of all participants scored above the cut-off for having a sleep disorder. Specifically, 26.8% scored on insomnia, 12.1% on sleep breathing disorders, 9.7% on hypersomnia, 13.7% on circadian rhythm sleep-wake disorders, 11.2% on parasomnia, and 17.9% on sleep-related movement disorders. Most sleep disorders were associated with greater severity of psychopathology and lower well-being. These associations got stronger with an increasing number of sleep disorders. Our study revealed higher suspected prevalence of most sleep disorders in a mental disorder sample compared to the general population. Moreover, the presence of sleep disorder(s) was strongly associated with symptom severity and reduced well-being. These findings extend the notion that early detection and treatment of sleep disorders in mental health populations is essential for psychiatric outcome.

Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats.

Mania is a serious neuropsychiatric condition associated with significant morbidity and mortality. Previous studies have suggested that environmental exposures can contribute to mania pathogenesis. We measured dietary exposures in a cohort of individuals with mania and other psychiatric disorders as well as in control individuals without a psychiatric disorder. We found that a history of eating nitrated dry cured meat but not other meat or fish products was strongly and independently associated with current mania (adjusted odds ratio 3.49, 95% confidence interval (CI) 2.24-5.45, p < 8.97 × 10-8). Lower odds of association were found between eating nitrated dry cured meat and other psychiatric disorders. We further found that the feeding of meat preparations with added nitrate to rats resulted in hyperactivity reminiscent of human mania, alterations in brain pathways that have been implicated in human bipolar disorder, and changes in intestinal microbiota. These findings may lead to new methods for preventing mania and for developing novel therapeutic interventions.

Deletion of translin (Tsn) induces robust adiposity and hepatic steatosis without impairing glucose tolerance.

OBJECTIVE: Translin knockout (KO) mice display robust adiposity. Recent studies indicate that translin and its partner protein, trax, regulate the microRNA and ATM kinase signaling pathways, both of which have been implicated in regulating metabolism. In the course of characterizing the metabolic profile of these mice, we found that they display normal glucose tolerance despite their elevated adiposity. Accordingly, we investigated why translin KO mice display this paradoxical phenotype. METHODS: To help distinguish between the metabolic effects of increased adiposity and those of translin deletion per se, we compared three groups: (1) wild-type (WT), (2) translin KO mice on a standard chow diet, and (3) adiposity-matched WT mice that were placed on a high-fat diet until they matched translin KO adiposity levels. All groups were scanned to determine their body composition and tested to evaluate their glucose and insulin tolerance. Plasma, hepatic, and adipose tissue samples were collected and used for histological and molecular analyses. RESULTS: Translin KO mice show normal glucose tolerance whereas adiposity-matched WT mice, placed on a high-fat diet, do not. In addition, translin KO mice display prominent hepatic steatosis that is more severe than that of adiposity-matched WT mice. Unlike adiposity-matched WT mice, translin KO mice display three key features that have been shown to reduce susceptibility to insulin resistance: increased accumulation of subcutaneous fat, increased levels of circulating adiponectin, and decreased Tnfα expression in hepatic and adipose tissue. CONCLUSIONS: The ability of translin KO mice to retain normal glucose tolerance in the face of marked adipose tissue expansion may be due to the three protective factors noted above. Further studies aimed at defining the molecular bases for this combination of protective phenotypes may yield new approaches to limit the adverse metabolic consequences of obesity.

The clinical relevance of early identification and treatment of sleep disorders in mental health care: protocol of a randomized control trial.

BACKGROUND: Sleep disorders are a risk factor for developing a variety of mental disorders, have a negative impact on their remission rates and increase the risk of relapse. Early identification and treatment of sleep disorders is therefore of paramount importance. Unfortunately, in mental health care sleep disorders are often poorly recognized and specific treatment frequently occurs late or not at all. This protocol-paper presents a randomized controlled trial investigating the clinical relevance of early detection and treatment of sleep disorders in mental health care. The two aims of this project are 1) to determine the prevalence of sleep disorders in different mental disorders, and 2) to investigate the contribution of early identification and adequate treatment of sleep disorders in individuals with mental disorders to their sleep, mental disorder symptoms, general functioning, and quality of life. METHODS: Patients newly referred to a Dutch mental health institute for psychiatric treatment will be screened for sleep disorders with the self-assessment Holland Sleep Disorders Questionnaire (HSDQ). Patients scoring above the cut-off criteria will be invited for additional diagnostic evaluation and, treatment of the respective sleep disorder. Participants will be randomly assigned to two groups: Immediate sleep diagnostics and intervention (TAU+SI-T0), or delayed start of sleep intervention (TAU+SI-T1; 6 months after inclusion). The effect of sleep treatment as add-on to treatment as usual (TAU) will be tested with regard to sleep disorder symptoms, general functioning, and quality of life (in collaboration with a psychiatric sleep centre). DISCUSSION: This trial will examine the prevalence of different sleep disorders in a broad range of mental disorders, providing information on the co-occurrence of specific sleep and mental disorders. Further, this study is the first to investigate the impact of early treatment of sleep disorders on the outcome of many mental disorders. Moreover, standard sleep interventions will be tailored to specific mental disorders, to increase their efficacy. The results of this trial may contribute considerably to the improvement of mental health care. TRIAL REGISTRATION: This clinical trial has been retrospectively registered in the Netherlands Trial Register (NL8389; https://www.trialregister.nl/trial/8389) on February 2th, 2020.

Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study.

We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r=0.884, r=0.574, r=0.707 and r=0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r=-0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2=0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r=0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.

The effects of scheduled running wheel access on binge-like eating behavior and its consequences.

Binge eating disorder (BED) is an eating disorder involving repeated, intermittent over consumption of food in brief periods of time, usually with no compensatory behaviors. There are few successful treatments and the underlying neural mechanisms remain unclear. In the current study, we hypothesized that voluntary running wheel (RW) activity could reduce binge-like eating behavior in a rat model. Rats were given intermittent (3 times/wk) limited (1hr) access to a high-fat food (Crisco), in addition to continuously available chow. Crisco was available every Mon, Wed, and Fri for 1hr before dark onset. Rats were divided into 2 groups: those with RW access during the first half of the experiment and sedentary during the second half (RW-SED) and those that were sedentary during the first half of the experiment and had RW access during the second half (SED-RW). Crisco intake was significantly less in both groups during the period of time with a RW present. Within the bingeing RW-SED rats, the gene expression of the orexigenic neuropeptides AgRP and NPY were similar to a non-bingeing sedentary control (CON) group, while the expression of the anorexigenic neuropeptide POMC was significantly increased relative to the SED-RW and CON groups. Despite elevated POMC, the rats continued to binge. Additionally, within both groups, the gene expression of the D2R and Oprm1 in the NAc and the VTA were altered suggesting that the reward system was stimulated by both the bingeing behavior and the running wheel activity. Overall, access to a RW and the resulting activity significantly reduced binge-like behavior as well as modulated the effects of binging on brain appetite and reward systems.

Corticosterone administration in drinking water decreases high-fat diet intake but not preference in male rats.

One of the mechanisms through which regular exercise contributes to weight maintenance could be by reducing intake and preference for high-fat (HF) diets. Indeed, we previously demonstrated that wheel-running rats robustly reduced HF diet intake and preference. The reduced HF diet preference by wheel running can be so profound that the rats consumed only the chow diet and completely avoided the HF diet. Because previous research indicates that exercise activates the hypothalamic-pituitary-adrenal axis and increases circulating levels of corticosterone, this study tested the hypothesis that elevation of circulating corticosterone is involved in wheel running-induced reduction in HF diet preference in rats.Experiment 1 measured plasma corticosterone levels under sedentary and wheel-running conditions in the two-diet-choice (high-carbohydrate chow vs. HF) feeding regimen. The results revealed that plasma corticosterone is significantly increased and positively correlated with the levels of running in wheel-running rats with two-diet choice.Experiments 2 and 3 determined whether elevated corticosterone without wheel running is sufficient to reduce HF diet intake and preference. Corticosterone was elevated by adding it to the drinking water. Compared with controls, corticosterone-drinking rats had reduced HF diet intake and body weight, but the HF diet preference between groups did not differ. The results of this study support a role for elevated corticosterone on the reduced HF diet intake during wheel running. The elevation of corticosterone alone, however, is not sufficient to produce a robust reduction in HF diet preference.

Exposure to activity-based anorexia impairs contextual learning in weight-restored rats without affecting spatial learning, taste, anxiety, or dietary-fat preference.

UNLABELLED: Relapse rates are high amongst cases of anorexia nervosa (AN) suggesting that some alterations induced by AN may remain after weight restoration. OBJECTIVE: To study the consequences of AN without confounds of environmental variability, a rodent model of activity-based anorexia (ABA) can be employed. We hypothesized that exposure to ABA during adolescence may have long-term consequences in taste function, cognition, and anxiety-like behavior after weight restoration. METHODS: To test this hypothesis, we exposed adolescent female rats to ABA (1.5 h food access, combined with voluntary running wheel access) and compared their behavior to that of control rats after weight restoration was achieved. The rats were tested for learning/memory, anxiety, food preference, and taste in a set of behavioral tests performed during the light period. RESULTS: Our data show that ABA exposure leads to reduced performance during the novel object recognition task, a test for contextual learning, without altering performance in the novel place recognition task or the Barnes maze, both tasks that test spatial learning. Furthermore, we do not observe alterations in unconditioned lick responses to sucrose nor quinine (described by humans as "sweet" and "bitter," respectively). Nor Do we find alterations in anxiety-like behavior during an elevated plus maze or an open field test. Finally, preference for a diet high in fat is not altered. DISCUSSION: Overall, our data suggest that ABA exposure during adolescence impairs contextual learning in adulthood without altering spatial leaning, taste, anxiety, or fat preference.

Similarities and differences between "proactive" and "passive" stress-coping rats in responses to sucrose, NaCl, citric acid, and quinine.

A stress-coping style describes a set of behavioral and physiological measures that characterize an individual's response to stressful stimuli. It would follow that different stress-coping styles are associated with differential sensitivity for taste stimuli. Animals with stress-coping characteristics better suited to an environment in which new foods are more frequently encountered may show enhanced orosensitivity to cues that signal toxins and/or nutritional value. Here, rats were categorized as "proactive" or "passive" based on results from a defensive burying test. Next, the brief-access taste procedure was used to compare unconditioned licking responses to a concentration array of compounds that humans describe as "sweet" (sucrose), "salty" (NaCl), "sour" (citric acid), and "bitter" (quinine) across the 2 groups. Both groups displayed concentration-dependent lick responses to sucrose, NaCl, citric acid, and quinine. The passive group initiated significantly fewer trials to sucrose than the proactive rats, but the groups did not significantly differ in trial initiation for the other 3 test compounds. Thus, differences in food intake, body weight, and glucose homeostasis between the stress-coping styles are not likely driven by alterations in orosensory responsivity. However, the current findings lend support to the hypothesis that the 2 groups differ in reward-related signaling mechanisms.

Early postweaning exercise improves central leptin sensitivity in offspring of rat dams fed high-fat diet during pregnancy and lactation.

Maternal high-fat (HF) diet has long-term consequences on the metabolic phenotype of the offspring. Here, we determined the effects of postweaning exercise in offspring of rat dams fed HF diet during gestation and lactation. Pregnant Sprague-Dawley rats were maintained on chow or HF diet throughout gestation and lactation. All pups were weaned onto chow diet on postnatal day (PND) 21. At 4 wk of age, male pups were given free access to running wheels (RW) or remained sedentary (SED) for 3 wk, after which all rats remained sedentary, resulting in four groups: CHOW-SED, CHOW-RW, HF-SED, and HF-RW. Male HF offspring gained more body weight by PND7 compared with CHOW pups and maintained this weight difference through the entire experiment. Three weeks of postweaning exercise did not affect body weight gain in either CHOW or HF offspring, but reduced adiposity in HF offspring. Plasma leptin was decreased at the end of the 3-wk running period in HF-RW rats but was not different from HF-SED 9 wk after the exercise period ended. At 14 wk of age, intracerebroventricular injection of leptin suppressed food intake in CHOW-SED, CHOW-RW, and HF-RW, while it did not affect food intake in HF-SED group. At death, HF-RW rats also had higher leptin-induced phospho-STAT3 level in the arcuate nucleus than HF-SED rats. Both maternal HF diet and postweaning exercise had effects on hypothalamic neuropeptide and receptor mRNA expression in adult offspring. Our data suggest that postweaning exercise improves central leptin sensitivity and signaling in this model.

Forced and voluntary exercise counteract insulin resistance in rats: the role of coping style.

There are large individual differences in the success rates of exercise intervention programs aimed at the prevention and treatment of obesity-related disorders. In the present study, we tested the hypothesis that differences in coping style may impact the success rates of these intervention programs. We tested insulin responses before and after voluntary wheel running in both passive (insulin resistant) Roman Low Avoidance (RLA) and proactive (insulin sensitive) Roman High Avoidance (RHA) rats using intravenous glucose tolerance tests (IVGTTs). To control for a potential difference between voluntary and forced exercise, we also included RLA and RHA rats that were subjected to forced running. We found the following: 1) when given the opportunity to run voluntarily in a running wheel, passive RLA rats run more than proactively than RHA rats; 2) voluntary exercise leads to a normalization of insulin responses during an IVGTTs in RLA rats; and 3) there were no behavioral and physiological differences in efficacy between voluntary and forced running. We conclude that exercise, both forced and voluntary, is a successful lifestyle intervention for the treatment of hyperinsulinemia, especially in individuals with a passive coping style.

Effectivity of (Personalized) Cognitive Behavioral Therapy for Insomnia in Mental Health Populations and the Elderly: An Overview.

Insomnia is very prevalent in psychiatry and is considered a transdiagnostic symptom of mental disorders. Yet, it is not only a consequence of a mental condition but may also exert detrimental effects on psychiatric symptom severity and therapeutic response; thus, adequate insomnia treatment is particularly important in psychiatric populations. The first choice of intervention is cognitive behavioral therapy for insomnia (CBT-I) as it is rather effective, also in the long run without side effects. It is offered in various forms, ranging from in-person therapy to internet-delivered applications. CBT-I protocols are typically developed for individuals with insomnia disorder without co-occurring conditions. For an optimal therapeutic outcome of CBT-I in individuals with comorbid mental disorders, adaptations of the protocol to tailor the treatment might be beneficial. Based on a literature search using major search engines (Embase; Medline; APA Psych Info; and Cochrane Reviews), this paper provides an overview of the effectiveness of the different CBT-I applications in individuals with diverse comorbid mental conditions and older adults and describes the functionality of CBT-I protocols that have been personalized to specific psychiatric populations, such as depression, substance abuse, and schizophrenia spectrum disorder. Finally, we discuss urgent needs for insomnia therapy targeted to improve both sleep and psychopathologies.

Effect of early-life stress or fluoxetine exposure on later-life conditioned taste aversion learning in Sprague-Dawley rats.

In rodents, early-life exposure to environmental stress or antidepressant medication treatment has been shown to induce similar long-term consequences on memory- and depression-related behavior in adulthood. To expand on this line of work, we evaluated how juvenile exposure to chronic variable stress (CVS) or the selective serotonin reuptake inhibitor fluoxetine (FLX) influences conditioned taste aversion (CTA) learning in adulthood. To do this, in Experiment 1, we examined how adolescent CVS alone (postnatal day [PND] 35-48), or with prenatal stress (PNS) history (PNS + CVS), influenced the acquisition and extinction of CTA in adult male Sprague Dawley rats. Specifically, at PND70+ (adulthood), rats were presented with 0.15 % saccharin followed by an intraperitoneal (i.p.) injection of lithium chloride (LiCl) to induce visceral malaise. A total of four saccharin (conditioned stimulus) and LiCl (unconditioned stimulus) pairings occurred across the CTA acquisition phase. Next, saccharin was presented without aversive consequences, and intake was measured across consecutive days of the extinction phase. No differences in body weight gain across the experimental days, rate of CTA acquisition, or extinction of CTA, were observed among the experimental groups (control, n = 7; CVS, n = 12; PNS + CVS, n = 9). In Experiment 2, we evaluated if early-life FLX exposure alters CTA learning in adulthood. Specifically, adolescent stress naïve male and female rats received FLX (0 or 20 mg/kg/i.p) once daily for 15 consecutive days (PND35-49). During antidepressant exposure, FLX decreased body weight gain in both male (n = 7) and female rats (n = 7), when compared to respective controls (male control, n = 8; female control, n = 8). However, juvenile FLX exposure decreased body weight-gain in adult male, but not female, rats. Lastly, adolescent FLX history had no effect on CTA acquisition or extinction in adulthood (PND70), in neither male nor female rats. Together, the data indicate that juvenile FLX exposure results in a long-term decrease of body weight-gain in a male-specific manner. Yet, independent of sex, neither early-life stress nor FLX exposure alters CTA learning in adulthood.

Insomnia disorder and its reciprocal relation with psychopathology.

Sleep is crucial for daytime functioning. In populations with psychiatric conditions, many people suffer from insomnia symptoms or an insomnia disorder. Emerging evidence suggests a bidirectional relationship between insomnia and various psychopathologies, implying that insomnia not only may be a consequence of mental disorders but also may contribute to new development, symptom severity, and reoccurrence of diverse mental disorders. Research on potential mechanisms underlying the insomnia psychopathology association is important, both from the preventive and treatment perspective. Most hypotheses concern the influence of insomnia on emotion regulation and on shared pathophysiological pathways, ranging from gut microbiome composition to genetic and specific neurotransmitter system aberrations.

Fluoxetine and environmental enrichment similarly reverse chronic social stress-related depression- and anxiety-like behavior, but have differential effects on amygdala gene expression.

The adverse effects of stress on brain and behavior have long been known and well-studied, with abundant evidence linking stress to, among other things, mood and anxiety disorders. Likewise, many have investigated potential treatments for stress-related mood and anxiety phenotypes and demonstrated good response to standard antidepressant medications like selective serotonin reuptake inhibitors (SSRIs), as well as environmental manipulations like exercise or enrichment. However, the extent to which stress and various treatments act on overlapping pathways in the brain is less well understood. Here, we used a widely studied social defeat stress paradigm to induce a robust depression- and anxiety-like phenotype and chronic corticosterone elevation that persisted for at least 4 weeks in wild type male mice. When mice were treated with either the SSRI fluoxetine or an enriched environment, both led to similar behavioral recovery from social defeat. We then focused on the amygdala and assessed the effects of social defeat, fluoxetine, and enrichment on 168 genes broadly related to synaptic plasticity or oxidative stress. We found 24 differentially expressed genes in response to social defeat stress. Interestingly, fluoxetine led to broad normalization of the stress-induced expression pattern while enrichment led to expression changes in a separate set of genes. Together, this study provides additional insight into the chronic effects of social defeat stress on behavior and gene expression in the amygdala. The findings also suggest that, for a subset of genes assessed, fluoxetine and environmental enrichment have strikingly divergent effects on expression in the amygdala, despite leading to similar behavioral outcomes.

Role of miR-181c in Diet-induced obesity through regulation of lipid synthesis in liver.

We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene mt-COX1 and influence obesity-induced cardiac dysfunction through the mitochondrial pathway. Because liver plays a pivotal role during obesity, we hypothesized that miR-181c might contribute to the pathophysiological complications associated with obesity. Therefore, we used miR-181c/d-/- mice to study the role of miR-181c in hepatocyte lipogenesis during diet-induced obesity. The mice were fed a high-fat (HF) diet for 26 weeks, during which indirect calorimetric measurements were made. Quantitative PCR (qPCR) was used to examine the expression of genes involved in lipid synthesis. We found that miR-181c/d-/- mice were not protected against all metabolic consequences of HF exposure. After 26 weeks, the miR-181c/d-/- mice had a significantly higher body fat percentage than did wild-type (WT) mice. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d-/- mice. miR-181c/d-/- mice fed the HF diet had higher serum and liver triglyceride levels than did WT mice fed the same diet. qPCR data showed that several genes regulated by isocitrate dehydrogenase 1 (IDH1) were more upregulated in miR-181c/d-/- liver than in WT liver. Furthermore, miR-181c delivered in vivo via adeno-associated virus attenuated the lipogenesis by downregulating these same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.

The neurobiology of circadian rhythms.

PURPOSE OF REVIEW: There is growing awareness of the importance of circadian rhythmicity in various research fields. Exciting developments are ongoing in the field of circadian neurobiology linked to sleep, food intake, and memory. With the current knowledge of critical 'clock genes' (genes found to be involved in the generation of circadian rhythms) and novel techniques for imaging cyclic events in brain and peripheral tissue, this field of research is rapidly expanding. We reviewed only some of the highlights of the past year, and placed these findings into a mutual circadian perspective. RECENT FINDINGS: Recent findings on the organization of the circadian clock systems are addressed, ranging from the retina to the suprachiasmatic nucleus and peripheral organs. Novel developments in sleep, food intake, and memory research linked to circadian aspects are discussed. SUMMARY: The neurobiology of circadian rhythms is pivotal to the orchestration of the temporal organization of an individual's physiology and behavior. Endogenous circadian timing systems underlie coupling and uncoupling mechanisms of many neuronal and physiological processes, the latter possibly inducing health risks to the organism. The integration of sleep, food intake and memory in a circadian setting has clear potential as a systems neurobiology line of research.

Maternal high-fat diet results in cognitive impairment and hippocampal gene expression changes in rat offspring.

Consumption of a high-fat diet has long been known to increase risk for obesity, diabetes, and the metabolic syndrome. Further evidence strongly suggests that these same metabolic disorders are associated with an increased risk of cognitive impairment later in life. Now faced with an expanding global burden of obesity and increasing prevalence of dementia due to an aging population, understanding the effects of high-fat diet consumption on cognition is of increasingly critical importance. Further, the developmental origins of many adult onset neuropsychiatric disorders have become increasingly clear, indicating a need to investigate effects of various risk factors, including diet, across the lifespan. Here, we use a rat model to assess the effects of maternal diet during pregnancy and lactation on cognition and hippocampal gene expression of offspring. Behaviorally, adult male offspring of high-fat fed dams had impaired object recognition memory and impaired spatial memory compared to offspring of chow-fed dams. In hippocampus, we found decreased expression of Insr, Lepr, and Slc2a1 (GLUT1) among offspring of high-fat fed dams at postnatal day 21. The decreased expression of Insr and Lepr persisted at postnatal day 150. Together, these data provide additional evidence to suggest that maternal exposure to high-fat diet during pregnancy and lactation can have lasting effects on the brain, behavior, and cognition on adult offspring.

Early Changes in Adipose Tissue Morphology, Gene Expression, and Metabolism After RYGB in Patients With Obesity and T2D.

CONTEXT: Roux-en-Y gastric bypass (RYGB) surgery effectively prevents or treats type 2 diabetes (T2D). Adipose tissue (AT) mechanisms may be of importance. OBJECTIVE: To assess the relationship between early changes in whole-body and AT metabolism in surgically treated patients with T2D. DESIGN AND SETTING: A randomized single-center study. PATIENTS: Nineteen patients with T2D with body mass index 30 to 45 kg/m2. INTERVENTIONS: Thirteen patients were assessed at baseline and 4 and 24 weeks after RYGB (preceded by a 4-week low-calorie diet) and compared with 6 control patients continuing standard medical treatment: oral glucose tolerance test, subcutaneous AT biopsies for gene expression, adipocyte size, glucose uptake, lipolysis, and insulin action. RESULTS: At 4 and 24 weeks post-RYGB, all patients but one had stopped diabetes medication. Fasting glucose, HbA1c, and insulin levels decreased and the Matsuda index increased compared with baseline (P < 0.01 for all), indicating improved whole-body insulin sensitivity. Mean adipocyte size significantly reduced, more at 4 than at 24 weeks; at 4 weeks, glucose uptake per adipocyte was lowered, and isoproterenol-stimulated lipolysis tended to increase, whereas the fold insulin effects on glucose uptake and lipolysis were unchanged. Expression of genes involved in fatty acid oxidation, CPT1b and adiponectin, was increased at 4 weeks, whereas leptin and E2F1 (involved in cell proliferation) were reduced (P < 0.05 for all). CONCLUSION: Glycemic control and in vivo insulin sensitivity improved 4 weeks after RYGB, but adipocyte insulin sensitivity did not change despite a marked reduction in adipocyte size. Thus, mechanisms for a rapid improvement of T2D after RYGB may occur mainly in other tissues than adipose.