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Lactoferrin (LF) is an iron-binding glycoprotein exerting several physiological functions such as antimicrobial activity, modulatory effects on lipid metabolism and anti-inflammatory properties. We examined whether LF prevents diet-induced obesity and development of fatty liver formation in C57Bl/6J mice. Lactoferrin (15% of dietary casein replaced by LF) enhanced weight loss and decreased body fat content during energy restriction compared to casein without influencing energy intake. During the ad libitum feeding after weight loss, LF suppressed weight regain and protected against the development of fatty liver formation compared to casein without influencing energy intake or fecal fat excretion. During the weight regain phase LF also improved glucose tolerance, decreased skeletal muscle leptin mRNA expression, and ameliorated adipose tissue inflammation. In conclusion , LF supplementation enhances the outcome of weight loss and subsequent weight regain, ameliorates fatty liver formation, and exerts beneficial effects on glucose tolerance and adipocyte tissue inflammation without interfering energy intake.

We investigated the potential of a novel whey protein isolate (WPI) rich in lactoperoxidase, lactoferrin, growth factors and immunoglobulins, in the prevention and treatment of diet-induced obesity in C57Bl/6J mice. Compared with casein, WPI dose-dependently enhanced weight loss and decreased body fat content during energy restriction. WPI decreased hepatic S6 ribosomal protein phosphorylation and increased SIRT3 expression. WPI did not influence energy intake, apparent fat digestibility, or adipose tissue inflammation. Compared with casein, WPI dose-dependently prevented weight regain and protected against the development of fatty liver formation during ad libitum feeding after weight loss. WPI also modestly improved glucose tolerance. It was concluded that compared with casein, a diet based on WPI as protein source significantly improved outcome of weight loss and subsequent weight regain in high-fat-fed C57Bl/6J mice. The effects are mediated, at least partly, via inhibition of mTOR nutrient sensing pathway and activation of SIRT3 in the liver.

Background/Aims: The potential of whey protein and calcium to modify skeletal muscle gene expression during energy restriction (ER) was investigated in a model of diet-induced obesity. Methods: Obese C57BL/6J mice received casein (calcium 0.4%) and two different high-calcium (1.8%) whey protein-based [whey protein isolate (WPI) + Ca and α-lactalbumin + Ca] diets for ER. Results: Compared to casein, WPI and α-lactalbumin-based diets altered 208 and 287 genes, respectively, of which 186 genes were common to WPI and α-lactalbumin diets. These genes represented 31 KEGG pathways. The Wnt signaling was the most enriched pathway among the 101 genes regulated by α-lactalbumin only, whereas the 22 genes regulated by WPI only were not associated with KEGG pathways. Unlike casein, WPI and α-lactalbumin diets decreased Aldh1a7, Fasn, leptin, Nr4a3 and Scd1 mRNA expression, indicating dietary protein source-dependent alterations in muscle lipid and fatty acid metabolism. Muscle weight or lean body mass maintenance did not differ between groups although modest changes in hypertrophy/atrophy signaling were found. Conclusion: The skeletal muscle gene expression profile is modified by the dietary protein source and calcium during ER which may explain, at least in part, the greater anti-obesity effect of whey proteins and calcium compared to casein.

Obesity is frequently associated with endothelial dysfunction. We hypothesized that high-fat feeding dysregulates the balance between endothelial derived nitric oxide and superoxide formation. Furthermore, we examined whether caloric restriction could reverse the detrimental vascular effects related to obesity. Male C57Bl/6 mice were fed with normal-fat diet (fat 17%) or high-fat diet (fat 60%) for 150 days. After establishment of obesity at day 100, a subgroup of obese mice were put on caloric restriction (CR) (70% of ad libitum energy intake) for an additional 50 days. At day 100, aortic rings from obese mice receiving high-fat diet showed impaired endothelium-dependent vasodilation in response to acetylcholine (ACh). Caloric restriction reversed high-fat diet-induced endothelial dysfunction. At day 150, impaired vasodilatory responses to ACh in obese mice without caloric restriction were markedly improved by preincubation with the tetrahydrobiopterin (BH(4)) precursor sepiapterin and L-arginine, a substrate for endothelial nitric oxide synthase (eNOS). Additionally, inhibition of vascular arginase by L-norvaline partially, and superoxide scavenging by Tiron completely, restored endothelial cell function. Obese mice showed increased vascular superoxide production, which was diminished by endothelial denudation, pretreated of the vascular rings with apocynin (an inhibitor of reduced nicotinamide adenine dinucleotide phosphate [NADPH] oxidase), oxypurinol (an inhibitor of xanthine oxidase), N(G)-nitro-L-arginine methyl ester (LNAME; an inhibitor of eNOS), or by adding the BH(4) precursor sepiapterin. Caloric restriction markedly attenuated vascular superoxide production. In obese mice on CR, endothelial denudation increased superoxide formation whereas vascular superoxide production was unaffected by L-NAME. Western blot analysis revealed decreased phosphorylated eNOS (Ser1177)-to-total eNOS expression ratio in obese mice as compared to lean controls, whereas the phospho-eNOS/NOS ratio in obese mice on CR did not differ from the lean controls. In conclusion, the present study suggests that caloric restriction reverses obesity induced endothelial dysfunction and vascular oxidative stress, and underscores the importance of uncoupled eNOS in the pathogenesis.

Intracellular resistance (Ri), a raw measure of bioimpedance spectroscopy (BIS), has been suggested for assessment of muscle health. The associations of repeated BIS measurements with functioning and nutritional status were investigated in nursing home residents suffering from poor health and disabilities.A total of 106 nursing home residents (age 83±8 yrs, 75% women) were recruited. Whole body and calf BIS measures (lean body mass, resistance at 50 kHz, and Ri), height and calf electrode distance (D) were used to calculate six muscle indices. Hand grip and knee extension strengths were measured and data on Activities of Daily Living (ADL), mobility score, and Mini Nutritional Assessment (MNA) collected. Repeated measurements were performed at 3 (BIS) and 6 months (BIS, muscle strength, ADL, mobility, and MNA).All bioimpedance muscle indices were lower in women than men and associated with MNA. However, the calf skeletal muscle index (SMI=D2/Ri) associated with muscle strength measurements at baseline and consistently with mobility and ADL also at 6-month re-examination. When compared to the highest tertile of SMI percent change (cut point +0.7%), the patients in the lowest tertile (cut point - 11.6%) had a 5.3-fold risk (p=0.004) for mobility decline within the 6-month follow-up. This risk association also remained significant after controlling for age, gender, baseline mobility, and percent change in body weight.Calf intracellular resistance related to electrode distance is associated with the activities of daily living reflecting mobility in typical nursing home residents and a decrease in this index indicates a markedly increased risk for mobility decline.

Leucine-rich milk and whey proteins have been suggested for prevention of age related loss of muscle mass and strength i.e. sarcopenia. The effects of milk protein supplementation and low intensity home based physical exercise on body composition and muscle functions were investigated.A randomized double blind crossover trial.Community dwelling members of Helsinki rheumatoid association.Older people (N=47, mean age 69.5 years) suffering from polymyalgia rheumatica.Patients performed as many stand ups as possible twice a day after which they ingested a regular (Control) or a whey protein enriched dairy product with high leucine content (Test). The 8-week intervention periods were separated by a 4-week wash-out.Body composition was measured by dual x-ray absorptiometry and muscle functions by hand grip strength, force platform countermovement jump performance, chair stand test, and walking speed.The 16-week home-based post-exercise supplementation resulted in a 1.8% increase (p = 0.052) in lower limb muscle mass. Walking speed (+5.3%, p = 0.007) and chair stand test performance (-12.2 %, p0.001) were also improved. Furthermore, a tendency for increased jump power (+3.0%, p = 0.084) was observed. However, significant and consistent differences were not found in the changes of muscle mass indices or muscle functions between supplements, but the test supplement tended to prevent accumulation of body fat.A low intensity home based exercise program combined with post-exercise milk protein supplementation is feasible despite some gastrointestinal complaints and seems effective in improving the muscle mass and functions of older persons with a inflammatory disease. Further studies are needed to establish, whether and to what extent the use of leucine-enriched whey products prevent or treat age-associated sarcopenia and whether they are superior to the present commercial milk products.

Tripeptides isoleucyl-prolyl-proline (IPP) and valyl-prolyl-proline (VPP) act as ACE inhibitors in vitro. Double transgenic rats (dTGR) harbouring human renin and human angiotensinogen genes develop malignant hypertension due to increased angiotensin II formation. The present study was aimed to evaluate possible antihypertensive effect of IPP and VPP in this severe model. Four-week-old dTGR were randomized in three groups to receive: (1) water (control), (2) fermented milk containing IPP and VPP, and (3) IPP and VPP dissolved in water for three weeks. Fermented milk, but not peptides in water, attenuated the development of hypertension in dTGR by 19 mmHg versus the control group (P=.023). In vitro vascular function tests showed that high concentrations of the peptides evinced ACE inhibitory properties. In other hypertension related variables, no significant differences between the treatment groups were found. In conclusion, fermented milk product containing IPP and VPP prevents development of malignant hypertension in an animal model.

Background The glycaemic response to foods is dependent on the quality and content of carbohydrates. Carbohydrates in the form of dietary fibre have favourable effects on insulin and glucose metabolism and may help to control energy intake. Dairy products have a relatively low carbohydrate content, and most of the carbohydrate is in the form of lactose which causes gastrointestinal symptoms in part of the population. In order to avoid these symptoms, dairy products can be replaced with lactose-free dairy products which are on the market in many parts of the world. However, the effects of lactose-free products on insulin and glucose metabolism have not been studied. Methods In the present study, we investigated the effects of 1) a lactose-free milk drink, 2) a novel fibre-enriched, fat- and lactose-free milk drink and 3) normal fat-free milk on serum glucose and insulin levels and satiety using a randomized block design. Following an overnight fast, 26 healthy volunteers ingested 200 ml of one of these drinks on three non-consecutive days. Insulin and glucose levels and subjective satiety ratings were measured before the ingestion of the milk product and 20, 40, 60, 120 and 180 minutes after ingestion. The responses were calculated as the area under the curve subtracted by the baseline value (AUC minus baseline). Results The insulin response was significantly lower for the fibre-enriched milk drink than it was for the other milk products (AUC, P = 0.007). There were no differences in the response for glucose or in the AUC for the subjective satiety ratings between the studied milk products. Conclusion The present results suggest that this novel milk drink could have positive effects on insulin response.

The aim of the study was to compare the effect of different whey protein-containing high-Ca diets on weight loss and weight regain in a model of diet-induced obesity. Obesity was induced in C57BL/6J mice with a high-fat (60 % of energy) diet. Weight loss by energy restriction was performed on four different high-Ca diets (1·8 % CaCO3) containing different whey proteins (18 % of energy): α-lactalbumin (ALA), β-lactoglobulin (BLG), lactoferrin (LF) and whey protein isolate (WPI). After 7 weeks of energy restriction some of the mice were killed and the rest were fed with the same diets ad libitum for 7 weeks. The mice on the LF diet lost significantly more weight than mice on the WPI diet. The body fat content in the ALA and LF groups was significantly lower than in the WPI group (P P Ad libitum feeding after weight loss resulted in weight regain in all groups and only the ALA diet significantly reduced fat accumulation during weight regain. The weight regain was most pronounced in the LF group, but the adipocyte size was still significantly smaller than in the other groups. There were no differences in food intake or apparent fat digestibility between the groups. It can be concluded that a high-Ca diet with ALA significantly improves the outcome of weight loss and subsequent weight regain during the feeding of a high-fat diet in C57BL/6J mice, in comparison with WPI.

AIM: To characterise the effect of energy restriction (ER) on liver lipid and primary metabolite profile by using metabolomic approach. We also investigated whether the effect of energy restriction can be further enhanced by modification of dietary protein source and calcium. METHODS: Liver metabolomic profile of lean and obese C57Bl/6J mice (n = 10/group) were compared with two groups of weight-reduced mice. ER was performed on control diet and whey protein-based high-calcium diet (whey + Ca). The metabolomic analyses were performed using the UPLC/MS based lipidomic platform and the HPLC/MS/MS based primary metabolite platform. RESULTS: ER on both diets significantly reduced hepatic lipid accumulation and lipid droplet size, while only whey + Ca diet significantly decreased blood glucose (P < 0.001) and serum insulin (P < 0.01). In hepatic lipid species the biggest reduction was in the level of triacylglycerols and ceramides while the level of cholesterol esters was significantly increased during ER. Interestingly, diacylglycerol to phospholipid ratio, an indicator of relative amount of diabetogenic diglyceride species, was increased in the control ER group, but decreased in the whey + Ca ER group (P < 0.001, vs obese). ER on whey + Ca diet also totally reversed the obesity induced increase in the relative level of lipotoxic ceramides (P < 0.001, vs obese; P > 0.05, vs lean). These changes were accompanied with up-regulated TCA cycle and pentose phosphate pathway metabolites. CONCLUSION: ER-induced changes on hepatic metabolomic profile can be significantly affected by dietary protein source. The therapeutic potential of whey protein and calcium should be further studied.

Background/Aims: Calcium and dairy proteins have been postulated to explain why the intake of dairy products correlates inversely with body mass index in several populations. We have shown that a high-calcium diet with whey protein attenuates weight gain and now we describe the effects of this diet on adipose tissue gene expression. Methods: Nine-week-old C57Bl/6J mice were divided into two groups (n = 10/group). The control diet was a standard high-fat diet (60% of energy) low in calcium (0.4%). The whey protein diet was a high-calcium (1.8%), high-fat diet with whey protein. After the 21-week treatment, adipose tissue transcript profiling (2 mice/group) was performed using Affymetrix Mouse Genome 430 2.0. Results: The high-calcium diet with whey protein altered the expression of 129 genes (± 1.2 fold). Quantitative RT-PCR analysis confirmed the significant up-regulation of Adrb3 (p = 0.002) and leptin (p = 0.0019) in the high-calcium whey group. Insulin and adipocytokine signaling pathways were enriched among the up-regulated genes and the fatty acid metabolism pathway among the down-regulated genes. Conclusions: High-calcium diet with whey protein significantly modifies adipose tissue gene expression. These preliminary findings reveal that targets of a high-calcium diet with whey protein include genes for Adrb3 and leptin, and help to explain how the intake of dairy products might attenuate obesity.