Catherine W. Yeckel

Nutrient Selection in the Absence of Taste Receptor Signaling

When allowed to choose between different macronutrients, most animals display a strong attraction toward carbohydrates compared with proteins. It remains uncertain, however, whether this food selection pattern depends primarily on the sensory properties intrinsic to each nutrient or, alternatively, metabolic signals can act independently of the hedonic value of sweetness to stimulate elevated sugar intake. Here we show that Trpm5 −/− mice, which lack the cellular mechanisms required for sweet and several forms of l-amino acid taste transduction, develop a robust preference for d-glucose compared with isocaloric l-serine independently of the perception of sweetness. Moreover, a close relationship was found between glucose oxidation and taste-independent nutrient intake levels, with animals increasing intake as a function of glucose oxidation rates. Furthermore, microdialysis measurements revealed nutrient-specific dopaminergic responses in accumbens and dorsal striatum during intragastric infusions of glucose or serine. Specifically, intragastric infusions of glucose induced significantly higher levels of dopamine release compared with isocaloric serine in both ventral and dorsal striatum. Intragastric stimulation of dopamine release seemed to depend on glucose utilization, because administration of an anti-metabolic glucose analog resulted in lower dopamine levels in striatum, an effect that was reversed by intravenous glucose infusions. Together, our findings suggest that carbohydrate-specific preferences can develop independently of taste quality or caloric load, an effect associated with the ability of a given nutrient to regulate glucose metabolism and stimulate brain dopamine centers.

Short‐term metabolic and cardiovascular effects of metformin in markedly obese adolescents with normal glucose tolerance

Objective:  Although metformin (MET) is an insulin sensitizer currently used as an adjunct to the treatment of some of the complications of childhood obesity besides type 2 diabetes mellitus, few studies have comprehensively examined its metabolic and clinical effects in obese children with normal glucose tolerance (NGT).

The gut-brain dopamine axis: a regulatory system for caloric intake.

Post-ingestive factors are known to strongly modulate feeding behavior by providing feedback signals to the central nervous system on the current physiological state of the organism. Of particular interest is the identification of the physiological pathways that permit the brain to sense post-ingestive signals. We will review recent evidence supporting the concept that direct stimulation of the gastrointestinal tract with nutrients induces release of the catecholamine neurotransmitter dopamine. In addition, changes in dopamine efflux produced by direct stimulation of the gastrointestinal tract were found to reflect the caloric load of the infusates, suggesting that dopamine signaling may function as a central caloric sensor that mediates adjustments in intake according to the caloric density of a meal. Consistent with the above, blockade of dopamine signaling disrupts flavor-nutrient associations and impairs the regulatory capacity to maintain constant caloric intake during intra-gastric feeding. Future research must determine the exact pathways linking gut nutrient administration to dopamine efflux. Current evidence points to parallel contributions by pre- and post-absorptive pathways, indicating that dopamine systems constitute a site of convergence through which distinct physiological signals can exert control over ingestive behaviors.

Regulation of fat intake in the absence of flavour signalling

•  The hedonic orosensory properties of fats strongly promote intake, but it remains unknown whether fat intake stimulates brain reward circuits in the absence of orosensory cues. •  We developed a behavioral assay that allows for the dissociation between orosensory versus post‐oral influences on fat intake. •  Mice trained to lick a dry spout to receive intra‐gastric infusions of fat emulsions maintained constant caloric intake in response to changes in energy density or hunger levels. •  Dopamine levels in dorsal and ventral striatum were responsive to gut infusions of fat emulsions, in such a way that (1) extracellular striatal dopamine levels fluctuate in proportion to the caloric density of nutrients infused in the gut; and (2) inhibiting dopamine receptor signalling disrupts the animals’ ability to maintain constant caloric intake across experimental sessions. •  Our results support the existence of a gut–brain dopamine axis that functions as a flavour‐independent central sensor of fat calories.

Glucose utilization rates regulate intake levels of artificial sweeteners

•  Much remains to be determined regarding the physiological signals and brain systems that mediate the attribution of greater reward to sugars compared to artificial sweeteners. •  We show that disruption of glucose utilization in mice produces an enduring inhibitory effect on artificial sweetener intake. •  Consistently, hungry mice shifted their preferences away from artificial sweeteners and in favour of glucose after experiencing glucose in a hungry state. •  Disrupting glucose oxidation suppressed dorsal striatum dopamine efflux during sugar intake. •  Glucose oxidation controls intake levels of sweet tastants by modulating extracellular dopamine levels in dorsal striatum.

Effects of ad libitum Ingestion of Monosodium Glutamate on Weight Gain in C57BL6/J Mice

Although the umami compound monosodium glutamate (MSG) is a widely used flavor enhancer, controversy still persists regarding the effects of MSG intake on body weight. It has been claimed, in particular, that chronic MSG intake may result in excessive body weight gain and obesity. In this study we assessed the effects of chronic (16 weeks) ad libitum MSG on body weight and metabolism of C57BL6/J mice. Adult male mice were divided in four experimental groups and fed with either a low-fat (LF) or high-fat (HF) diet and with either two bottles of plain water or one bottle containing 1% MSG and another one containing water according to a factorial design. Mice were monitored weekly for body weight and food/fluid intake for 15 weeks. At the end of the experiments, the circulating levels of leptin, insulin, total protein, total cholesterol, triglyceride, blood urea nitrogen, and non-esterified fatty acids were also analyzed. Our results show that MSG intake did not influence body weight in either LF or HF groups. Interestingly, although animals overall displayed strong preferences for MSG against water, preferences were relatively higher in LF compared to HF group. Consistent with the body weight data, while significant differences in leptin, insulin, total cholesterol, and non-esterified fatty acids were found between HF and LF groups, such an effect was not influenced by MSG intake. Finally, indirect calorimetry measurements revealed similar energy expenditure levels between animals being presented water only and MSG only. In summary, our data does not support the notion that ad libitum MSG intake should trigger the development of obesity or other metabolic abnormalities.

The Impact of Ventilation and Early Diagnosis on Tuberculosis Transmission in Brazilian Prisons

Prisoners have among the highest incidence of tuberculosis (TB) globally. However, the contribution of the prison environment on transmission is not well understood and structural characteristics have received little attention as effective epidemiological interventions in TB control. We evaluated architectural characteristics and estimated ventilation rates in 141 cells in three prisons in central west Brazil using steady-state exhaled carbon dioxide (CO2) levels. We used a modified Wells-Riley equation to estimate the probability of infection for inmates sharing a cell with an infectious case and projected the impact of interventions, including early diagnosis and improved ventilation. Overall, prison cells were densely populated (mean 2.1 m(2) per occupant) and poorly ventilated, with only three cells meeting World Health Organization (WHO) standards for per-person ventilation (60 L/s) applied in infection control settings. In the absence of interventions, projected mean risk of infection was 78.0% during a 6-month period. Decreasing time-to-diagnosis by 25% reduced transmission risk by 8.3%. Improving ventilation to WHO standards decreased transmission by 38.2%, whereas optimizing cross-ventilation reduced transmission by 64.4%. Prison environments promote high infection risk over short-time intervals. In this context, enhanced diagnostics have a limited impact on reducing transmission. Improving natural ventilation may be required to effectively control TB in prisons.

Imaging human brown adipose tissue under room temperature conditions with 11C-MRB, a selective norepinephrine transporter PET ligand

INTRODUCTION Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with (11)C-MRB ((S,S)-(11)C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. METHODS Ten healthy, Caucasian subjects (5 M: age 24.6±2.6, BMI 21.6±2.7kg/m(2); 5 F: age 25.4±2.1, BMI 22.1±1.0kg/m(2)) underwent (11)C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15°C) compared to (18)F-FDG PET-CT imaging. Uptake of (11)C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. RESULTS As expected, (18)F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT (11)C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0±0.3 vs. cold 1.1±0.3, p=0.31; BAT/muscle DVR: RT 2.3±0.7 vs. cold 2.5±0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of (11)C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with (18)F-FDG (p=0.63). Furthermore, there were gender differences in (11)C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in (11)C-MRB as a function of both body composition and body temperature. CONCLUSIONS Unlike (18)F-FDG, the uptake of (11)C-MRB in BAT offers a unique opportunity to investigate the role of BAT in humans under basal, room temperature conditions.

A pilot study: the importance of inter-individual differences in inorganic arsenic metabolism for birth weight outcome.

Inorganic arsenic (iAs) exposure is detrimental to birth outcome. We lack information regarding the potential for iAs metabolism to affect fetal growth. Our pilot study evaluated postpartum Romanian women with known birth weight outcome for differences in iAs metabolism. Subjects were chronically exposed to low-to-moderate drinking water iAs. We analyzed well water, arsenic metabolites in urine, and toenail arsenic. Urine iAs and metabolites, toenail iAs, and secondary methylation efficiency increased as an effect of exposure (p<0.001). Urine iAs and metabolites showed a significant interaction effect between exposure and birth weight. Moderately exposed women with low compared to normal birth weight outcome had greater metabolite excretion (p<0.03); 67% with low compared to 10% with normal birth weight outcome presented urine iAs >9 μg/L (p=0.019). Metabolic partitioning of iAs toward excretion may impair fetal growth. Prospective studies on iAs excretion before and during pregnancy may provide a biomarker for poor fetal growth risk.

Abdominal obesity in older women: potential role for disrupted fatty acid reesterification in insulin resistance.

CONTEXT Excess abdominal adiposity is a primary factor for insulin resistance in older age. OBJECTIVES Our objectives were to examine the role of abdominal obesity on adipose tissue, hepatic, and peripheral insulin resistance in aging, and to examine impaired free fatty acid metabolism as a mechanism in these relations. DESIGN This was a cross-sectional study. SETTING The study was performed at a General Clinical Research Center. PARTICIPANTS Healthy, inactive older (>60 yr) women (n = 25) who were not on hormone replacement therapy or glucose-lowering medication were included in the study. Women with abdominal circumference values above the median (>97.5 cm) were considered abdominally obese. MAIN OUTCOME MEASURES Whole-body peripheral glucose utilization, adipose tissue lipolysis, and hepatic glucose production were measured using in vivo techniques according to a priori hypotheses. RESULTS In the simple analysis, glucose utilization at the 40 mU insulin dose (6.3 +/- 2.8 vs. 9.1 +/- 3.4; P < 0.05), the index of the insulin resistance of basal hepatic glucose production (23.6 +/- 13.0 vs. 15.1 +/- 6.0; P < 0.05), and insulin-stimulated suppression of lipolysis (35 vs. 54%; P < 0.05) were significantly different between women with and without abdominal obesity, respectively. Using the glycerol appearance rate to free fatty acid ratio as an index of fatty acid reesterification revealed markedly blunted reesterification in the women with abdominal adiposity under all conditions: basal (0.95 +/- 0.29 vs. 1.35 +/- 0.47; P < 0.02); low- (2.58 +/- 2.76 vs. 6.95 +/- 5.56; P < 0.02); and high-dose (4.46 +/- 3.70 vs. 12.22 +/- 7.13; P < 0.01) hyperinsulinemia. Importantly, fatty acid reesterification was significantly (P < 0.01) associated with abdominal circumference and hepatic and peripheral insulin resistance, regardless of total body fat. CONCLUSION These findings support the premise of dysregulated fatty acid reesterification with abdominal obesity as a pathophysiological link to perturbed glucose metabolism across multiple tissues in aging.