Fasting oxyntomodulin, glicentin, and gastric inhibitory polypeptide levels are associated with activation of reward- and attention-related brain centres in response to visual food cues in adults with obesity: A cross-sectional functional MRI study.

Postprandial increases in gastrointestinal hormones are associated with reduced energy intake, partially through direct effects on the brain. However, it remains unknown whether the fasting levels of gastrointestinal hormones are associated with altered brain activity in response to visual food stimuli. We therefore performed a whole-brain regression cross-sectional analysis to assess the association between fasting brain activations according to functional magnetic resonance imaging, performed during viewing of highly desirable versus less desirable food images, with fasting levels of five gastrointestinal hormones (glucagon-like peptide [GLP]-1, GLP-2, oxyntomodulin, glicentin and gastric inhibitory polypeptide [GIP]) in 36 subjects with obesity. We observed that fasting blood levels of GIP were inversely associated with the activation of attention-related areas (visual cortices of the occipital lobe, parietal lobe) and of oxyntomodulin and glicentin with reward-related areas (insula, putamen, caudate for both, and additionally orbitofrontal cortex for glicentin) and the hypothalamus when viewing highly desirable as compared to less desirable food images. Future studies are needed to confirm whether fasting levels of oxyntomodulin, glicentin and GIP are associated with the activation of brain areas involved in appetite regulation and with energy intake in people with obesity.

Short-term treatment with high dose liraglutide improves lipid and lipoprotein profile and changes hormonal mediators of lipid metabolism in obese patients with no overt type 2 diabetes mellitus: a randomized, placebo-controlled, cross-over, double-blind clinical trial.

OBJECTIVE: Long-term treatment with up to 1.8 mg liraglutide improves cardiovascular and all-cause mortality in patients with type 2 diabetes at high risk for cardiovascular disease (CVD) and is currently under investigation in subjects without diabetes. Aim of our study was to investigate whether high dose (3 mg) short-term (5 weeks) treatment with liraglutide in obese patients with no overt type 2 diabetes affects metabolites, lipid and lipoprotein profile and components of activin-follistatin axis in cardiovascular beneficial or detrimental way. RESEARCH DESIGN AND METHODS: Twenty obese patients participated in a randomized, placebo-controlled, cross-over, double-blind study and were administrated liraglutide 3 mg or placebo for 5 weeks. Metabolites, fatty acids, lipid-lipoprotein profile and concentrations of activins and follistatins (250 parameters) were assessed in serum at start and completion of each treatment. RESULTS: Concentrations of important cardiovascular markers such as total, free and remnant cholesterol were reduced with liraglutide before and after adjusting for weight loss. Similarly, reductions in number of small and medium size LDL particles and in their total lipid concentration were observed with liraglutide and partially weight-loss related. Tyrosine levels were reduced and behenic acid levels were increased whereas only minor changes were observed in HDL, VLDL and IDL. Concentrations of activin AB and follistatin were significantly reduced in liraglutide-treated group. CONCLUSIONS: Treatment of obese patients without overt type 2 diabetes with high dose of liraglutide for a short period of time induces changes in lipid-lipoprotein and hormonal profile that are suggestive of lower risk of atherosclerosis and CVD. Trial registration ClinicalTrials.gov Identifier: NCT02944500. Study ID Number 2015P000327. Registered November 2016.

Circulating ApoJ is closely associated with insulin resistance in human subjects.

OBJECTIVE: Insulin resistance is a major risk factor for type 2 diabetes. ApolipoproteinJ (ApoJ) has been implicated in altered pathophysiologic states including cardiovascular and Alzheimer's disease. However, the function of ApoJ in regulation of glucose homeostasis remains unclear. This study sought to determine whether serum ApoJ levels are associated with insulin resistance in human subjects and if they change after interventions that improve insulin sensitivity. METHODS: Serum ApoJ levels and insulin resistance status were assessed in nondiabetic (ND) and type 2 diabetic (T2D) subjects. The impacts of rosiglitazone or metformin therapy on serum ApoJ levels and glucose disposal rate (GDR) during a hyperinsulinemic/euglycemic clamp were evaluated in a separate cohort of T2D subjects. Total ApoJ protein or that associated with the HDL and LDL fractions was measured by immunoblotting or ELISA. RESULTS: Fasting serum ApoJ levels were greatly elevated in T2D subjects (ND vs T2D; 100±8.3 vs. 150.6±8.5AU, P<0.0001). Circulating ApoJ levels strongly correlated with fasting glucose, fasting insulin, HOMA-IR, and BMI. ApoJ levels were significantly and independently associated with HOMA-IR, even after adjustment for age, sex, and BMI. Rosiglitazone treatment in T2D subjects resulted in a reduction in serum ApoJ levels (before vs. after treatment; 100±13.9 vs. 77±15.2AU, P=0.015), whereas metformin had no effect on ApoJ levels. The change in ApoJ levels during treatment was inversely associated with the change in GDR. Interestingly, ApoJ content in the LDL fraction was inversely associated with HOMA-IR. CONCLUSION: Serum ApoJ levels are closely correlated with the magnitude of insulin resistance regardless of obesity, and decrease along with improvement of insulin resistance in response only to rosiglitazone in type 2 diabetes.

Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: A randomized, placebo-controlled, crossover study.

BACKGROUND: GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics. BASIC PROCEDURES: Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17days (0.6mg for 7days, 1.2mg for 7days and 1.8mg for 3days) of treatment, we also studied changes in fMRI responses to food cues. MAIN FINDINGS: By design, to avoid any confounding by weight changes, subjects were studied for 17days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA. PRINCIPAL CONCLUSIONS: We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that could over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials.

Differential Effects of Oral and Intravenous Lipid Administration on Key Molecules Related to Energy Homeostasis.

CONTEXT: The spectrum of lipid-induced changes in the secretion of hormones important in energy homeostasis has not yet been fully elucidated. OBJECTIVE: To identify potential incretin-like effects in response to lipid administration, we examined the short-term effect of iv vs oral lipids on key molecules regulating energy homeostasis. Design, Intervention, and Participants: After a 10-hour overnight fast, 26 subjects were randomized to receive an oral lipid load, a 10% iv lipid emulsion, a 20% iv lipid emulsion, or an iv saline infusion. We obtained blood samples at 30-minute intervals for the first 2 hours and hourly thereafter for a total of 6 hours. MAIN OUTCOME MEASURES: Circulating levels of insulin, glucose, c-peptide, free fatty acids, incretins (glucagon-like peptide-1, gastric inhibitory polypeptide), glucagon, peptide YY, ghrelin, fibroblast growth factor 21, fetuin A, irisin, omentin, and adiponectin were measured. RESULTS: Oral lipid ingestion resulted in higher glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, and peptide YY levels, compared with the other three groups (incremental area under the curve P = .003, P < .001, P < .001, P < .001, respectively). The 20% lipid emulsion, leading to higher free fatty acid levels, resulted in greater insulin, c-peptide, and fibroblast growth factor 21 responses compared with placebo and the other two groups (incremental area under the curve P = .002, P = .005, P < .001, P < .001, respectively). Omentin, adiponectin, fetuin A, and irisin levels were not affected by either mode of lipid administration. CONCLUSIONS: Metabolic responses to lipids depend on the route of administration. Only iv lipids trigger a dose-dependent fibroblast growth factor 21 secretion, which is nonglucagon mediated. Intravenous lipids also induce hyperinsulinemia without concurrent decreases in glucose, a phenomenon observed in insulin-resistant states. Orally administered lipids mostly affect gastrointestinal tract-secreted molecules important in glucose and energy homeostasis such as glucagon, incretins, and peptide YY.

Early life adversity and/or posttraumatic stress disorder severity are associated with poor diet quality, including consumption of trans fatty acids, and fewer hours of resting or sleeping in a US middle-aged population: A cross-sectional and prospective study.

BACKGROUND: Early life adversity (ELA) and post-traumatic stress disorder (PTSD) are associated with poorer psychological and physical health. Potential underlying mechanisms and mediators remain to be elucidated, and the lifestyle habits and characteristics of individuals with ELA and/or PTSD have not been fully explored. We investigated whether the presence of ELA and/or PTSD are associated with nutrition, physical activity, resting and sleeping and smoking. METHODS: A cross-sectional sample of 151 males and females (age: 45.6±3.5 years, BMI: 30.0±7.1 kg/m(2)) underwent anthropometric measurements, as well as detailed questionnaires for dietary assessment, physical activity, resting and sleeping, smoking habits and psychosocial assessments. A prospective follow-up visit of 49 individuals was performed 2.5 years later and the same outcomes were assessed. ELA and PTSD were evaluated as predictors, in addition to a variable assessing the combined presence/severity of ELA-PTSD. Data were analyzed using analysis of covariance after adjusting for several socioeconomic, psychosocial and anthropometric characteristics. RESULTS: Individuals with higher ELA or PTSD severity were found to have a poorer diet quality (DASH score: p=0.006 and p=0.003, respectively; aHEI-2010 score: ELA p=0.009), including further consumption of trans fatty acids (ELA p=0.003); the differences were significantly attenuated null after adjusting mainly for education or income and/or race. Further, individuals with higher ELA severity reported less hours of resting and sleeping (p=0.043) compared to those with zero/lower ELA severity, and the difference remained significant in the fully adjusted model indicating independence from potential confounders. When ELA and PTSD were combined, an additive effect was observed on resting and sleeping (p=0.001); results remained significant in the fully adjusted model. They also consumed more energy from trans fatty acids (p=0.017) tended to smoke more (p=0.008), and have less physical activity (PTSD p=0.024) compared to those with no or lower ELA and PTSD severity. Adjustments for sociodemographic factors and/or BMI rendered results of the above lifestyle parameters non-significant. The analysis of the prospective data showed similar trends to the cross-sectional analysis, further supporting the conclusions, although statistical significance of results was lower due to the lower number of participants. CONCLUSION: Fewer hours of resting and sleeping and poorer diet quality are linked to ELA and/or PTSD, indicating that these pathways might underlie the development of several metabolic abnormalities in individuals with ELA and/or PTSD. Differences in terms of diet quality are significantly attenuated by race and/or education and/or income, whereas differences in other lifestyle habits of individuals with and without ELA and/or PTSD, such as physical activity, are mostly explained by confounding sociodemographic variables and/or body mass index.