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Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. [Pmch.sup.-/-] rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in [pmch.sup.-/-] rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e., the first 8 postnatal weeks. Loss of Pinch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pinch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development and indicate that the MCH receptor 1 system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries. melanin-concentrating hormone; hypothalamus: childhood obesity; rat knockout model doi:10.1152/ajpendo.00154.2009.

Background: Lifestyle intervention studies to treat type 2 diabetes (T2D) are on the rise. However, in‐depth research is lacking into the dietary changes that participants make. Methods: The present study aimed to observe the dietary intake of participants following the group program 'Reverse Diabetes2 Now' (RD2N) over 12 months. The web‐based 24‐h dietary recall‐tool Compl‐eat was used to collect dietary intake data. Results: In total, 147 T2D patients were included in a cross‐sectional study (n = 37 at baseline, n = 58 at 6 months, n = 52 at 12 months). A lower intake of total energy, carbohydrates and iodine was found for the groups at 6 and 12 months compared to the baseline group. The absolute consumption of total fat and saturated fat did not differ between the groups; only the percentage as total calorie consumption decreased. Consumption of vegetables and full‐fat yoghurt was higher in groups at 6 and 12 months compared to the group at baseline. Consumption of bread, cakes and sweet biscuits, pasta/rice/tortillas, artificially sweetened soft drinks, and crisps were lower in the groups at 6 and 12 months compared to the group at baseline. Similar results were observed in a separate prospective study in 22 participants over 12 months following the same lifestyle‐intervention. Conclusions: Overall, participants shifted their dietary intake somewhat towards a healthier dietary pattern with overall lower energy and carbohydrates and more vegetables. Moreover, participants largely maintained this healthier pattern over 12 months. There were some concerns regarding iodine intake. These promising results need to be confirmed in a fully‐scaled study, as well in a comparison with controls. Key points: Participants who followed the group program 'Reverse Diabetes2 Now' and who participated in this observational study shifted their dietary intake somewhat towards a healthier dietary pattern with overall lower energy and carbohydrates and more vegetables.Participants largely maintained this healthier pattern over 12 months.These promising results need to be confirmed in a fully‐scaled study as well as in a comparison with controls. [ABSTRACT FROM AUTHOR]

There is substantial evidence in the literature that elevated plasma free fatty acids (FFA) play a role in the pathogenesis of type 2 diabetes. CVT-3619 is a selective partial [A.sub.1] adenosine receptor agonist that inhibits lipolysis and lowers circulating FFA. The present study was undertaken to determine the effect of CVT-3619 on insulin resistance induced by high-fat (HF) diet in rodents. HF diet feeding to rats for 2 wk caused a significant increase in insulin, FFA, and triglyceride (TG) concentrations compared with rats fed chow. CVT-3619 (1 mg/kg) caused a time-dependent decrease in fasting insulin, FFA, and TG concentrations. Acute administration of CVT-3619 significantly lowered the insulin response, whereas glucose response was not different with an oral glucose tolerance test. Treatment with CVT-3619 for 2 wk resulted in significant lowering of FFA, TG, and insulin concentrations in rats on HF diet. To determine the effect of CVT-3619 on insulin sensitivity, hyperinsulinemic euglycemic clamp studies were performed in C57BL/J6 mice fed HF diet for 12 wk. Glucose infusion rate was decreased significantly in HF mice compared with chow-fed mice. CVT-3619 treatment 15 min prior to the clamp study significantly (P < 0.01) increased glucose infusion rate to values similar to that for chow-fed mice. In conclusion, CVT-3619 treatment lowers FFA and TG concentrations and improves insulin sensitivity in rodent models of insulin resistance. CVT-3619; antilipolytic; free fatty acids; triglycerides; oral glucose tolerance test doi:10.1152/ajpendo.00573.2006

[PYY.sub.3-36] is a gut-derived hormone acting on hypothalamic nuclei to inhibit food intake. We recently showed that [PYY.sub.3-36] acutely reinforces insulin action on glucose disposal in mice. We aimed to evaluate effects of [PYY.sub.3-36] on energy metabolism and the impact of chronic [PYY.sub.3-36] treatment on insulin sensitivity. Mice received a single injection of [PYY.sub.3-36] or were injected once daily for 7 days, and energy metabolism was subsequently measured in a metabolic cage. Furthermore, the effects of chronic [PYY.sub.3-36] administration (continuous and intermittent) on glucose turnover were determined during a hyperinsulinemic-euglycemic clamp. [PYY.sub.3-36] inhibited cumulative food intake for 30 min of refeeding after an overnight fast (0.29 [+ or -] 0.04 vs. 0.56 [PYY.sub.3-36] 0.12 g, P = 0.036) in an acute setting, but not after 7 days of daily dosing. Body weight, total energy expenditure, and physical activity were not affected by [PYY.sub.3-36]. However, it significantly decreased the respiratory quotient. Both continuous and intermittent [PYY.sub.3-36] treatment significantly enhanced insulin-mediated whole body glucose disposal compared with vehicle treatment (81.2 [+ or -] 6.2 vs. 77.1 [+ or -] 5.2 vs. 63.4 [+ or -] 5.5 [micro]mol * [min.sup.-1] * [kg.sup.-1], respectively). In particular, [PYY.sub.3-36] treatment increased glucose uptake in adipose tissue, whereas its impact on glucose disposal in muscle did not attain statistical significance. [PYY.sub.3-36] treatment shifts the balance of fuel use in favor of fatty acids and enhances insulin sensitivity in mice, where it particularly promotes insulin-mediated glucose disposal. Notably, these metabolic effects of [PYY.sub.3-36] remain unabated after chronic administration, in contrast to its anorexic effects. diabetes; brain; metabolism; gut hormone

Insulin is an important inhibitor of both hepatic glucose output and hepatic VLDL-triglyceride (VLDL-TG) production. We investigated whether both processes are equally sensitive to insulin-mediated inhibition. To test this, we used euglycemic clamp studies with four increasing plasma concentrations of insulin in wild-type C57B1/6 mice. By extrapolation, we estimated that half-maximal inhibition of hepatic glucose output and hepatic VLDL-TG production by insulin were obtained at plasma insulin levels of ~3.6 and ~6.8 ng/ml, respectively. In the same experiments, we measured that half-maximal decrease of plasma free fatty acid levels and half-maximal stimulation of peripheral glucose uptake were reached at plasma insulin levels of ~3.0 and ~6.0 ng/ml, respectively. We conclude that, compared with insulin sensitivity of hepatic glucose output, peripheral glucose uptake and hepatic VLDL-TG production are less sensitive to insulin. very-low-density lipoprotein; fatty acid; euglycemic hyperinsulinemic clamp; liver

Author(s): Mihai G Netea (corresponding author) [1, 2, 8]; Leo A B Joosten [3, 8]; Eli Lewis [2]; Dalan R Jensen [4]; Peter J Voshol [5]; Bart Jan Kullberg [1]; [...]

Kok, Petra, Madelon M. Buijs, Simon W. Kok, Inge H. A. P. van Ierssel, Marijke Frolich, Ferdinand Roelfsema, Peter J. Voshol, A. Edo Meinders, and Hanno Pijl. Acipimox enhances spontaneous growth hormone secretion in obese women. Am J Physiol Regul Integr Comp Physiol 286: R693-R698, 2004. First published December 11, 2003; 10.1152/ajpregu.00595.2003.--We hypothesized that a high circulating free fatty acid (FFA) concentration is involved in the pathogenesis of hyposomatotropism associated with obesity. To evaluate this hypothesis, 10 healthy premenopausal women (body mass index 33.8 [+ or -] 1.0 kg/[m.sup.2]) were studied in the follicular phase of their menstrual cycle at two occasions with a time interval of at least 8 wk, where body weight remained stable. Subjects were randomly assigned to treatment with either acipimox (an inhibitor of lipolysis, 250 mg orally 4 times daily) or placebo in a double-blind crossover design, starting 1 day before admission until the end of the blood sampling period. Blood samples were taken during 24 h with a sampling interval of 10 min for assessment of growth hormone (GH) concentrations, and GH secretion was estimated by deconvolution analysis. Identical methodology was used to study GH secretion in a historical control group of age-matched normal weight women. GH secretion was clearly blunted in obese women (total daily release 66 [+ or -] 10 vs. lean controls: 201 [+ or -] 23 mU * [[l.sub.Vd].sup.-1] * 24 [h.sup.-1], P = 0.005, where [l.sub.Vd] is liter of distribution volume). Acipimox considerably enhanced total (113 [+ or -] 50 vs. 66 [+or -] 10 mU * [[l.sub.Vd].sup.-1] * 24[h.sup.-1], P = 0.02) and pulsatile GH secretion (109 [+ or -] 49 vs. 62 [+ or -] 30 mU * [[l.sub.Vd].sup.-1] * 24 [h.sup.-1], P = 0.02), but GH output remained lower compared with lean controls. Further analysis did not show any relationship between the effects of acipimox on GH secretion and regional body fat distribution. In conclusion, acipimox unleashes spontaneous GH secretion in obese women. It specifically enhances GH secretory burst mass. This might mean that lowering of systemic FFA concentrations by acipimox modulates neuroendocrine mechanisms that orchestrate the activity of the somatotropic ensemble. hyposomatotropism; growth hormone kinetics; somatotroph cell function; free fatty acid

Dietary interventions with fish oil have been found to protect against the development of high-fat diet-induced insulin resistance and to decrease the expression of tumor necrosis factor (TNF)-[alpha]. However, the effect of fish oil administration on preexisting insulin resistance is subject to debate. In the present study, we examined the mechanism by which fish oil affects preexisting insulin resistance. High fat diet-induced insulin-resistant ApoE*3-Leiden transgenic mice were treated for 10 wk as follows: 1) high fat diet (control group), 2) high fat diet with 3 g/100 g fish oil and 3) high fat diet but food intake restricted to 75% of the ad libitum food intake. We measured plasma glucose, insulin, free fatty acids (FFA) and triglyceride (TG) levels throughout the study. After the 10-wk dietary intervention period we performed hyperinsulinemic euglycemic analyses and measured insulin sensitivity and FFA turnover. Furthermore, we then determined the VLDL-TG production rate and TNF-[alpha] protein expression in white adipose tissue (WAT). Compared with control mice, the insulin sensitivity of mice treated with fish oil was not affected, whereas it was improved (P < 0.05) for energy-restricted mice. FFA turnover was unaffected in both fish oil-treated and energy-restricted mice. Compared with controls, hepatic VLDL-TG production was lower (P < 0.05) with fish oil feeding but greater with energy restriction (P < 0.05). Interestingly, the level of TNF-[alpha] protein in WAT was lower (P < 0.05) in both groups. We conclude that partial replacement of saturated fat by fish oil does not improve preexisting high fat diet-induced insulin resistance, although it lowers TNF-[alpha] protein levels in WAT. KEY WORDS: * fish oil * insulin resistance * insulin sensitivity * free fatty acid metabolism * tumor necrosis factor-[alpha]