Hepatocyte growth factor regulates neovascularization in developing fat pads

In this study, we used lentiviral-delivered shRNA to generate a clonal line of 3T3-F442A preadipocytes with stable silencing of hepatocyte growth factor (HGF) expression and examined the long-term consequence of this modification on fat pad development. HGF mRNA expression was reduced 94%, and HGF secretion 79% (P < 0.01), compared with preadipocytes treated with nontargeting shRNA. Fat pads derived from HGF knockdown preadipocytes were significantly smaller (P < 0.01) than control pads beginning at 3 days postinjection (0.022 ± 0.003 vs. 0.037 ± 0.004 g), and further decreased in size at day 7 (0.015 ± 0.004 vs. 0.037 ± 0.003 g) and day 14 (0.008 ± 0.002 vs. 0.045 ± 0.007 g). Expression of the endothelial cell genes TIE1 and PECAM1 increased over time in control fat pads (1.6 ± 0.4 vs. 11.4 ± 1.7 relative units at day 3 and 14, respectively; P < 0.05) but not in HGF knockdown fat pads (1.1 ± 0.5 vs. 5.9 ± 2.2 relative units at day 3 and 14). Contiguous vascular structures were observed in control fat pads but were much less developed in HGF knockdown fat pads. Differentiation of preadipocytes to mature adipocytes was significantly attenuated in HGF knockdown fat pads. Fat pads derived from preadipocytes with knockdown of the HGF receptor c-MET were smaller than control pads at day 3 postinjection (0.034 ± 0.002 vs. 0.049 ± 0.004 g; P < 0.05), and remained the same size through day 14. c-MET knockdown fat pads developed a robust vasculature, and preadipocytes differentiated to mature adipocytes. Overall these data suggest that preadipocyte-secreted HGF is an important regulator of neovascularization in developing fat pads

Combination GLP-1 and Insulin Treatment Fails to Alter Myocardial Fuel Selection Versus Insulin Alone in Type 2 Diabetes

Context Glucagon-like peptide-1 (GLP-1) and the clinically available GLP-1 agonists have been shown to exert effects on the heart. It is unclear whether these effects occur at clinically used doses in vivo in humans, possibly contributing to CVD risk reduction. Objective To determine whether liraglutide at clinical dosing augments myocardial glucose uptake alone or in combination with insulin compared to insulin alone in metformin-treated Type 2 diabetes mellitus. Design Comparison of myocardial fuel utilization after 3 months of treatment with insulin detemir, liraglutide, or combination detemir+liraglutide. Setting Academic hospital Participants Type 2 diabetes treated with metformin plus oral agents or basal insulin. Interventions Insulin detemir, liraglutide, or combination added to background metformin Main Outcome Measures Myocardial blood flow, fuel selection and rates of fuel utilization evaluated using positron emission tomography, powered to demonstrate large effects. Results We observed greater myocardial blood flow in the insulin-treated groups (median[25th, 75th percentile]: detemir 0.64[0.50, 0.69], liraglutide 0.52[0.46, 0.58] and detemir+liraglutide 0.75[0.55, 0.77] mL/g/min, p=0.035 comparing 3 groups and p=0.01 comparing detemir groups to liraglutide alone). There were no evident differences between groups in myocardial glucose uptake (detemir 0.040[0.013, 0.049], liraglutide 0.055[0.019, 0.105], detemir+liraglutide 0.037[0.009, 0.046] µmol/g/min, p=0.68 comparing 3 groups). Similarly there were no treatment group differences in measures of myocardial fatty acid uptake or handling, and no differences in total oxidation rate. Conclusions These observations argue against large effects of GLP-1 agonists on myocardial fuel metabolism as mediators of beneficial treatment effects on myocardial function and ischemia protection

Adipocytes enhance murine pancreatic cancer growth via a hepatocyte growth factor (HGF)-mediated mechanism

INTRODUCTION: Obesity accelerates the development and progression of pancreatic cancer, though the mechanisms underlying this association are unclear. Adipocytes are biologically active, producing factors such as hepatocyte growth factor (HGF) that may influence tumor progression. We therefore sought to test the hypothesis that adipocyte-secreted factors including HGF accelerate pancreatic cancer cell proliferation. MATERIAL AND METHODS: Murine pancreatic cancer cells (Pan02 and TGP-47) were grown in a) conditioned medium (CM) from murine F442A preadipocytes, b) HGF-knockdown preadipocyte CM, c) recombinant murine HGF at increasing doses, and d) CM plus HGF-receptor (c-met) inhibitor. Cell proliferation was measured using the MTT assay. ANOVA and t-test were applied; p < 0.05 considered significant. RESULTS: Wild-type preadipocyte CM accelerated Pan02 and TGP-47 cell proliferation relative to control (59 ± 12% and 34 ± 12%, p < 0.01, respectively). Knockdown of preadipocyte HGF resulted in attenuated proliferation vs. wild type CM in Pan02 cells (35 ± 5% vs. 68 ± 14% greater than control; p < 0.05), but proliferation in TGP-47 cells remained unchanged. Recombinant HGF dose-dependently increased Pan02, but not TGP-47, proliferation (p < 0.05). Inhibition of HGF receptor, c-met, resulted in attenuated proliferation versus control in Pan02 cells, but not TGP-47 cells. CONCLUSIONS: These experiments demonstrate that adipocyte-derived factors accelerate murine pancreatic cancer proliferation. In the case of Pan02 cells, HGF is responsible, in part, for this proliferation

Retinopathy predicts progression of fasting plasma glucose: An Early Diabetes Intervention Program (EDIP) analysis

Background Retinopathy is increasingly recognized in prediabetic populations, and may herald increased risk of metabolic worsening. The Early Diabetes Intervention Program (EDIP) evaluated worsening of glycemia in screen-detected Type 2 diabetes, following participants for up to 5 years. Here we have evaluated whether the presence of retinopathy at the time of detection of diabetes was associated with accelerated progression of glycemia. Methods We prospectively studied 194 participants from EDIP with available baseline retinal photographs. Retinopathy was determined at baseline using 7-field fundus photography and defined as an Early Treatment of Diabetic Retinopathy Study Scale grading score of ≥ 20. Results At baseline, 12% of participants had classical retinal lesions indicating retinopathy. In univariate Cox proportional hazard analysis, the presence of retinopathy at baseline was associated with a doubled risk of progression of fasting plasma glucose (HR 2.02; 95% CI 1.05–3.89). The retinopathy effect was robust to individual adjustment for age and glucose, the most potent determinants of progression in EDIP. Conclusion Retinopathy was associated with increased risk of progression of fasting plasma glucose among adults with screen-detected, early diabetes. Early detection of retinopathy may help individualize more aggressive therapy to prevent progressive metabolic worsening in early diabetes

Correlation between Ventromedial Prefrontal Cortex Activation to Food Aromas and Cue-driven Eating: An fMRI Study

Food aromas are signals associated with both food's availability and pleasure. Previous research from this laboratory has shown that food aromas under fasting conditions evoke robust activation of medial prefrontal brain regions thought to reflect reward value (Bragulat, et al. 2010). In the current study, eighteen women (eleven normal-weight and seven obese) underwent a two-day imaging study (one after being fed, one while fasting). All were imaged on a 3T Siemens Trio-Tim scanner while sniffing two food (F; pasta and beef) odors, one non-food (NF; Douglas fir) odor, and an odorless control (CO). Prior to imaging, participants rated hunger and perceived odor qualities, and completed the Dutch Eating Behavior Questionnaire (DEBQ) to assess “Externality” (the extent to which eating is driven by external food cues). Across all participants, both food and non-food odors (compared to CO) elicited large blood oxygenation level dependent (BOLD) responses in olfactory and reward-related areas, including the medial prefrontal and anterior cingulate cortex, bilateral orbitofrontal cortex, and bilateral piriform cortex, amygdala, and hippocampus. However, food odors produced greater activation of medial prefrontal cortex, left lateral orbitofrontal cortex and inferior insula than non-food odors. Moreover, there was a significant correlation between the [F > CO] BOLD response in ventromedial prefrontal cortex and “Externality” sub-scale scores of the DEBQ, but only under the fed condition; no such correlation was present with the [NF > CO] response. This suggests that in those with high Externality, ventromedial prefrontal cortex may inappropriately valuate external food cues in the absence of internal hunger

Ghrelin is not Related to Hunger or Calories Consumed at Breakfast in Lean and Obese Women

poster abstractBackground: The mechanisms that result in greater caloric intake in obese individuals are incompletely understood. Ghrelin administration increases ad lib food intake in humans. We investigated the relationship of ghrelin to calorie consumption and hunger at breakfast on two separate occasions in lean and obese women. Methods: 23 lean (BMI 22.3±0.5 kg/m2, 26.5±1.0 yr) and 25 obese (BMI 36.9±0.7 kg/m2, 27.8±1.1 yr) women participated in a noncontiguous 2 day study. The minimum and maximum days between visits were 6 and 43 days. Participants were given the same breakfast on both days (turkey sausage, French toast with margarine/syrup, fruit cup, coffee, tea, diet soda, or water) with portions adjusted to provide 20% of the daily energy requirement for weight maintenance. Subjects were instructed to eat until full. Hunger was evaluated on a Satiety Labeled Intensity Magnitude Scale (SLIM) before and after the meal. Anchors were “greatest imaginable fullness” at 0 and “greatest imaginable hunger” at 100. Blood samples were collected over 120 minutes for measurement of active ghrelin. Results: Lean subjects consumed an equivalent number of calories on both days (380.0±14.6 vs 378.2±14.9 kcal), as did the obese (419.4±16.2 vs 428.8±15.4 kcal). On average for both days, obese consumed significantly more breakfast calories than lean (424.1±11.1 vs 379.1±10.3 kcal; P<0.01), but the same percentage of calories provided (85.7±1.8 vs 86.1±1.7 %kcal). Lean subjects rated hunger before breakfast the same on both days (69.2±1.6 vs 71.7±1.4), as did the obese (69.8±1.6 vs 69.6±1.8), and there was no difference between the groups. Lean subjects rated hunger after breakfast the same on both days (27.8±1.9 vs 30.3±2.4), as did the obese (25.0±1.7 vs 24.3±1.8). The reduction in hunger score following breakfast was significant for both groups (P<0.0001), with the obese reporting significantly less hunger/more fullness after breakfast than the lean (P=0.02). Fasting ghrelin was significantly greater in the lean than obese women (549.9±58.9 vs 231.0±29.1 pg/ml; P<0.0001). Ghrelin was significantly reduced at 60 min following breakfast in the lean (375.8±49.2 pg/ml; P=0.028) but not the obese (212.2±26.4 pg/ml). Ghrelin was not related to hunger score prior to breakfast, and there was no relationship between reduction in ghrelin and hunger score in the lean or obese. Conclusion: Caloric intake (as a percentage provided) and hunger scores before breakfast on two occasions were the same for both lean and obese women. Fasting ghrelin was significantly different between lean and obese women but did not predict hunger score or calories consumed. Our findings do not support a role for ghrelin in driving food intake at breakfast

Family history of alcoholism and the human brain response to oral sucrose

A heightened hedonic response to sweet tastes has been associated with increased alcohol preference and alcohol consumption in both humans and animals. The principal goal of this study was to examine blood oxygenation level dependent (BOLD) activation to high- and low-concentration sweet solutions in subjects who are either positive (FHP) or negative (FHN) for a family history of alcoholism. Seventy-four non-treatment seeking, community-recruited, healthy volunteers (22.8 ± 1.6 SD years; 43% men) rated a range of sucrose concentrations in a taste test and underwent functional magnetic resonance imaging (fMRI) during oral delivery of water, 0.83 M, and 0.10 M sucrose. Sucrose compared to water produced robust activation in primary gustatory cortex, ventral insula, amygdala, and ventral striatum. FHP subjects displayed greater bilateral amygdala activation than FHN subjects in the low sucrose concentration (0.10 M). In secondary analyses, the right amygdala response to the 0.10 M sucrose was greatest in FHP women. When accounting for group differences in drinks per week, the family history groups remained significantly different in their right amygdala response to 0.10 M sucrose. Our findings suggest that the brain response to oral sucrose differs with a family history of alcoholism, and that this response to a mildly reinforcing primary reward might be an endophenotypic marker of alcoholism risk

Acute and second-meal effects of almond form in impaired glucose tolerant adults: a randomized crossover trial

<p>Abstract</p> <p>Background</p> <p>Nut consumption may reduce the risk of developing type 2 diabetes. The aim of the current study was to measure the acute and second-meal effects of morning almond consumption and determine the contribution of different nut fractions.</p> <p>Methods</p> <p>Fourteen impaired glucose tolerant (IGT) adults participated in a randomized, 5-arm, crossover design study where whole almonds (WA), almond butter (AB), defatted almond flour (AF), almond oil (AO) or no almonds (vehicle - V) were incorporated into a 75 g available carbohydrate-matched breakfast meal. Postprandial concentrations of blood glucose, insulin, non-esterified free fatty acids (NEFA), glucagon-like peptide-1 (GLP-1) and appetitive sensations were assessed after treatment breakfasts and a standard lunch.</p> <p>Results</p> <p>WA significantly attenuated second-meal and daylong blood glucose incremental area under the curve (AUCI) and provided the greatest daylong feeling of fullness. AB and AO decreased blood glucose AUCI in the morning period and daylong blood glucose AUCI was attenuated with AO. WA and AO elicited a greater second-meal insulin response, particularly in the early postprandial phase, and concurrently suppressed the second-meal NEFA response. GLP-1 concentrations did not vary significantly between treatments.</p> <p>Conclusions</p> <p>Inclusion of almonds in the breakfast meal decreased blood glucose concentrations and increased satiety both acutely and after a second-meal in adults with IGT. The lipid component of almonds is likely responsible for the immediate post-ingestive response, although it cannot explain the differential second-meal response to AB versus WA and AO.</p

Mastication of Nuts under Realistic Eating Conditions: Implications for Energy Balance

The low digestibility and high satiety effects of nuts have been partly attributed to mastication. This work examines chewing forces and the bolus particle size of nuts (walnuts, almonds, pistachios) varying in physical properties under different conditions (with and without water, juice, sweetened yogurt and plain yogurt) along with satiety sensations and gut hormone concentrations following walnut consumption (whole or butter). In a randomized, cross-over design with 50 adults (25 males, 25 females; Body Mass Index (BMI) 24.7 ± 3.4 kg/m²; age: 18⁻52 years old (y/o), the chewing forces and particle size distribution of chewed nuts were measured under different chewing conditions. Appetite sensations were measured at regular intervals for 3 h after nut intake, and plasma samples were collected for the measurement of glucose, insulin and Glucagon-like peptide-1 (GLP-1). The three nuts displayed different particle sizes at swallowing though no differences in chewing forces were observed. Walnuts with yogurt yielded larger particle sizes than the other treatments. Particle size was not correlated with either food palatability or flavor. Fullness sensations were higher after whole nut than nut butter consumption though there were no significant changes in glucose, insulin, or GLP-1 concentrations under any condition. Changing the conditions at swallowing might influence the release of energy from nuts

The apéritif effect: Alcohol's effects on the brain's response to food aromas in women

OBJECTIVE: Consuming alcohol prior to a meal (an apéritif) increases food consumption. This greater food consumption may result from increased activity in brain regions that mediate reward and regulate feeding behavior. Using functional magnetic resonance imaging, we evaluated the blood oxygenation level dependent (BOLD) response to the food aromas of either roast beef or Italian meat sauce following pharmacokinetically controlled intravenous infusion of alcohol. METHODS: BOLD activation to food aromas in non-obese women (n = 35) was evaluated once during intravenous infusion of 6% v/v EtOH, clamped at a steady-state breath alcohol concentration of 50 mg%, and once during infusion of saline using matching pump rates. Ad libitum intake of roast beef with noodles or Italian meat sauce with pasta following imaging was recorded. RESULTS: BOLD activation to food relative to non-food odors in the hypothalamic area was increased during alcohol pre-load when compared to saline. Food consumption was significantly greater, and levels of ghrelin were reduced, following alcohol. CONCLUSIONS: An alcohol pre-load increased food consumption and potentiated differences between food and non-food BOLD responses in the region of the hypothalamus. The hypothalamus may mediate the interplay of alcohol and responses to food cues, thus playing a role in the apéritif phenomenon