Angiotensin converting enzyme inhibition lowers body weight and improves glucose tolerance in C57BL/6J mice maintained on a high fat diet

The renin–angiotensin system (RAS) is functional within adipose tissue and angiotensin II, the active component of RAS, has been implicated in adipose tissue hypertrophy and insulin resistance. In this study, captopril, an angiotensin converting enzyme (ACE) inhibitor that prevents angiotensin II formation, was used to study the development of diet-induced obesity and insulin resistance in obesity prone C57BL/6J mice. The mice were fed a high fat diet (w/w 21% fat) and allowed access to either water or water with captopril added (0.2 mg/ml). Body weight was recorded weekly and water and food intake daily. Glucose tolerance was determined after 11–12 weeks. On completion of the study (after 16 weeks of treatment), the mice were killed and kidney, liver, epididymal fat and extensor digitorum longus muscle (EDL) were weighed. Blood samples were collected and plasma analysed for metabolites and hormones. Captopril treatment decreased body weight in the first 2 weeks of treatment. Food intake of captopril-treated mice was similar to control mice prior to weight loss and was decreased after weight loss. Glucose tolerance was improved in captopril-treated mice. Captopril-treated mice had less epididymal fat than control mice. Relative to body weight, captopril-treated mice had increased EDL weight. Relative to control mice, mice administered captopril had a higher plasma concentration of adiponectin and lower concentrations of leptin and non-esterified fatty acids (NEFA). The results indicate that captopril both induced weight loss and improved insulin sensitivity. Thus, captopril may eventually be used for the treatment of obesity and Type 2 diabetes.

Differential effects of natural palm oil, chemically and enzymatically-modified palm oil on weight gain, blood lipid metabolites and fat deposition in a pediatric pig model

Background: Increasing prevalence of obesity and overweight in the Western world, continue to be a major health threat and is responsible for increased health care costs. Dietary intervention studies show a strong positive association between saturated fat intake and the development of obesity and cardiovascular disease. This study investigated the effect of positional distribution of palmitic acid (Sn-1, 2 & 3) of palm oil on cardiovascular health and development of obesity, using weaner pigs as a model for young children.

Methods: Male and female weaner piglets were randomly allocated to 4 dietary treatment groups: 1) pork lard (LRD); 2) natural palm olein (NPO); 3) chemically inter-esterified PO (CPO) and 4) enzymatically inter-esterified PO (EnPO) as the fat source. Diets were formulated with 11% lard or with palm olein in order to provide 31% of digestible energy from fat in the diet and were balanced for cholesterol, protein and energy across treatments.

Results: From 8 weeks onwards, pigs on EnPO diet gained (P < 0.05) more weight than all other groups. Feed conversion efficiency (feed to gain) over the 12 week experimental period did not vary between treatment groups. Plasma LDL-C content and LDL-C/HDL-C ratio in pigs fed natural PO tended to be lower compared to all other diets. The natural PO lowered (P < 0.02) the plasma triglyceride (TG) content relative to the lard or EnPO diets, but was not different from the CPO diet. The natural PO diet was associated with lower (P < 0.05) saturated fat levels in subcutaneous adipose tissue than the CPO and EnPO diets that had lower saturated fat levels than the lard diet. Female pigs had lower lean and higher fat and fat:lean ratio in the body compared with male pigs. No difference in weight gain or blood lipid parameters was observed between sexes.

Conclusions: The observations on plasma TG, muscle and adipose tissue saturated fatty acid contents and back fat (subcutaneous) thickness suggest that natural palm oil may reduce deposition of body fat. In addition, dietary supplementation with natural palm oil containing palmitic acid at different positions in meat producing animals may lead to the production of meat and meat products with lower saturated fats. An increase in fat content and a decrease in lean content in female pigs resulted in an increased body fat:lean ratio but gender had no effect on blood lipid parameters or insulin concentrations.

Hedgehog partial agonism drives warburg-lie metabolism in muscle and brown fat

Diabetes, obesity, and cancer affect upward of 15% of the world’s population. Interestingly, all three diseases juxtapose dysregulated intracellular signaling with altered metabolic state. Exactly which genetic factors define stable metabolic set points in vivo remains poorly understood. Here, we show that hedgehog signaling rewires cellular metabolism. We identify a cilium-dependent Smo-Ca2+-Ampk axis that triggers rapid Warburg-like metabolic reprogramming within minutes of activation and is required for proper metabolic selectivity and flexibility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of “selective partial agonists,” capable of concomitant inhibition of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-independent glucose uptake in muscle and brown adipose tissue. These data identify multiple noncanonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new therapeutic avenue for obesity and diabetes.

Interspecific variations in the gastrointestinal microbiota in penguins

Despite the enormous amount of data available on the importance of the gastrointestinal (GI) microbiota in vertebrate (especially mammals), information on the GI microbiota of seabirds remains incomplete. As with many seabirds, penguins have a unique digestive physiology that enables them to store large reserves of adipose tissue, protein, and lipids. This study used quantitative real-time polymerase chain reaction (qPCR) and 16S rRNA gene pyrosequencing to characterize the interspecific variations of the GI microbiota of four penguin species: the king, gentoo, macaroni, and little penguin. The qPCR results indicated that there were significant differences in the abundance of the major phyla Firmicutes, Bacteroides, Actinobacteria, and Proteobacteria. A total of 132,340, 18,336, 6324, and 4826 near full-length 16S rRNA gene sequences were amplified from fecal samples collected from king, gentoo, macaroni, and little penguins, respectively. A total of 13 phyla were identified with Firmicutes, Bacteroidetes, Proteobacteria, and Fusobacteria dominating the composition; however, there were major differences in the relative abundance of the phyla. In addition, this study documented the presence of known human pathogens, such as Campylobacter, Helicobacter, Prevotella, Veillonella, Erysipelotrichaceae, Neisseria, and Mycoplasma. However, their role in disease in penguins remains unknown. To our knowledge, this is the first study to provide an in-depth investigation of the GI microbiota of penguins.

The role of lipogenesis in the development of obesity and diabetes in Israeli sand rats (Psammomys obesus)

Obesity and diabetes in Israeli sand rats, Psammomys obesus, occur with the sequential transition of animals from normal insulin sensitivity to impaired insulin sensitivity, accompanied by increased adiposity, prior to insulin resistance and obesity, in a manner similar to susceptible human populations. The current study was designed to examine the role of de novo lipid synthesis in the development of excessive weight gain in P. obesus. Sand rats were classified at 12 wk of age into three groups: A, normoglycemic normoinsulinemic; B, normoglycemic hyperinsulinemic; C, hyperglycemic hyperinsulinemic, based on glucose and insulin responses in fed sand rats. Body weight, liver weight, white adipose tissue (WAT) mass and food intake were significantly elevated in Group C compared to Group A (P < 0.05). Lipogenic rate was measured by the amount of 3H incorporated into subscapular brown adipose tissue (BAT), epidiymal WAT and liver per hour, from sand rats with and without access to food. No difference in lipogenic rate was found between the groups in BAT, indicating that this tissue is of minor importance in whole body lipogenesis in P. obesus. In the WAT there was a greater lipogenic rate with the development of obesity and hyperinsulinemia (Group B vs. Group A) but no difference in the liver. However, the onset of hyperglycemia (Group C) further stimulated WAT lipogenesis and initiated increased hepatic lipogenesis, both of which contributed to the pre-existing obesity. This study suggests that elevated lipogenesis is not the primary cause of obesity in P. obesus, as lipogenic rate only markedly increases after obesity is already present in hyperglycemic animals.

Alcohol consumption and body composition in a population-based sample of elderly Australian men

Background: Alcohol is calorie dense, and impacts activity, appetite and lipid processing. The aim of this study was to therefore investigate the association between alcohol consumption and components of body composition including bone, fat and lean tissue.

Methods: Participants were recruited from a randomly selected, population-based sample of 534 men aged 65 years and older enrolled in the Geelong Osteoporosis Study. Alcohol intake was ascertained using a food frequency questionnaire and the sample categorised as nondrinkers or alcohol users who consumed B2, 3–4 or C5 standard drinks on a usual drinking day. Bone mineral density (BMD), lean body mass and body fat mass were measured using dual energy X-ray absorptiometry; overall adiposity (%body fat), central adiposity (%truncal fat) and body mass index (BMI) were calculated. Bone quality was determined by quantitative heel ultrasound (QUS).

Results: There were 90 current non-drinkers (16.9 %), 266 (49.8 %) consumed 1–2 drinks/day, 104 (19.5 %) 3–4 drinks/day and 74 (13.8 %) C5 drinks/day. Those consuming C5 drinks/day had greater BMI (?4.8 %), fat mass index (?20.1 %), waist circumference (?5.0 %), %body fat (?15.2 %) and proportion of trunk fat (?5.3 %) and lower lean mass (-5.0 %) than non-drinkers after adjustment for demographic and lifestyle factors. Furthermore, they were more likely to be obese than non-drinkers according to criteria based on BMI (OR = 2.83, 95 %CI 1.10–7.29) or waist circumference (OR = 3.36, 95 %CI 1.32–8.54). There was an inverse relationship between alcohol consumption and QUS parameters and BMD at the mid forearm site; no differences were detected for BMD at other skeletal sites.

Conclusion: Higher alcohol intake was associated with greater total and central adiposity and reduced bone quality.

Tumor progression locus 2 (Tpl2) deficiency does not protect against obesity-induced metabolic disease

Obesity is associated with a state of chronic low grade inflammation that plays an important role in the development of insulin resistance. Tumor progression locus 2 (Tpl2) is a serine/threonine mitogen activated protein kinase kinase kinase (MAP3K) involved in regulating responses to specific inflammatory stimuli. Here we have used mice lacking Tpl2 to examine its role in obesity-associated insulin resistance. Wild type (wt) and tpl22/2 mice accumulated comparable amounts of fat and lean mass when fed either a standard chow diet or two different high fat (HF) diets containing either 42% or 59% of energy content derived from fat. No differences in glucose tolerance were observed between wt and tpl22/2 mice on any of these diets. Insulin tolerance was similar on both standard chow and 42% HF diets, but was slightly impaired in tpl22/2 mice fed the 59% HFD. While gene expression markers of macrophage recruitment and inflammation were increased in the white adipose tissue of HF fed mice compared with standard chow fed mice, no differences were observed between wt and tpl2 mice. Finally, a HF diet did not increase Tpl2 expression nor did it activate Extracellular Signal-Regulated Kinase 1/2 (ERK1/2), the MAPK downstream of Tpl2. These findings argue that Tpl2 does not play a non-redundant role in obesity associated metabolic dysfunction.

Metabolic remodelling in obesity and type 2 diabetes: pathological or protective mechanisms in response to nutrient excess?

Altered metabolism in tissues such as the liver, skeletal muscle and adipose tissue is observed in metabolic diseases characterized by nutrient excess and energy imbalance, such as obesity and type 2 diabetes. These alterations in metabolism can include resistance to the hormone insulin, lipid accumulation, mitochondrial dysfunction and transcriptional remodelling of major metabolic pathways. The underlying assumption has been that these same alterations in metabolism are fundamental to the pathogenesis of metabolic diseases. An alternative view is that these alterations in metabolism occur to protect cell and tissue viability in the face of constant positive energy balance. This speculative review presents evidence that many of the metabolic adaptations that occur in metabolic diseases characterized by nutrient excess can be viewed as protective in nature, rather than pathogenic per se for disease progression. Finally, we also briefly discuss the usefulness and potential pitfalls of therapeutic approaches that attempt to correct these same metabolic defects when energy balance is not altered, and the potential links between metabolic survival responses and other chronic diseases such as cancer.

Postexercise muscle cooling enhances gene expression of PGC-1α

This study aimed to investigate the influence of localized muscle cooling on postexercise vascular, metabolic, and mitochondrial-related gene expression.

Specific role of dietary fat in modifying cardiovascular and locomotor activity 24-h rhythms

Meal-fed conscious rabbits normally exhibit postprandial elevation in blood pressure, heart rate (HR) and locomotor activity, which is abolished by consumption of a high-fat diet (HFD). Here, we assessed whether the cardiovascular changes are attributable to the increased caloric intake due to greater fat content or to hyperphagia. Rabbits were meal-fed during the baseline period then maintained on either an ad libitum normal fat diet (NFD) or ad libitum HFD for 2 weeks. Blood pressure, HR and locomotor activity were measured daily by radio-telemetry alongside food intake and body weight. Caloric intake in rabbits given a NFD ad libitum rose 50% from baseline but there were no changes in cardiovascular parameters. By contrast, HR increased by 10% on the first day of the ad libitum HFD (p<0.001) prior to any change in body weight while blood pressure increased 7% after 4d (p<0.01) and remained elevated. Baseline 24-h patterns of blood pressure and HR were closely associated with mealtime, characterised by afternoon peaks and morning troughs. When the NFD was changed from meal-fed to ad libitum, blood pressure and HR did not change but afternoon activity levels decreased (p<0.05). By contrast, after 13d ad libitum HFD, morning HR, blood pressure and activity increased by 20%, 8% and 71%, respectively. Increased caloric intake specifically from fat, but not as a result of hyperphagia, appears to directly modulate cardiovascular homeostasis and circadian patterns, independent of white adipose tissue accumulation.

Flying, fasting, and feeding in birds during migration: a nutritional and physiological ecology perspective

Unlike exercising mammals, migratory birds fuel very high intensity exercise (e.g., flight) with fatty acids delivered from the adipose tissue to the working muscles by the circulatory system. Given the primary importance of fatty acids for fueling intense exercise, we discuss the likely limiting steps in lipid transport and oxidation for exercising birds and the ecological factors that affect the quality and quantity of fat stored in wild birds. Most stored lipids in migratory birds are comprised of three fatty acids (16:0, 18:1 and 18:2) even though migratory birds have diverse food habits. Diet selection and selective metabolism of lipids play important roles in determining the fatty acid composition of birds which, in turn, affects energetic performance during intense exercise. As such, migratory birds offer an intriguing model for studying the implications of lipid metabolism and obesity on exercise performance. We conclude with a discussion of the energetic costs of migratory flight and stopover in birds, and its implications for bird migration strategies.

Hormonal and metabolic responses to repeated cycling sprints under different hypoxic conditions

OBJECTIVE: Sprint exercise and hypoxic stimulus during exercise are potent factors affecting hormonal and metabolic responses. However, the effects of different hypoxic levels on hormonal and metabolic responses during sprint exercise are not known. Here, we examined the effect of different hypoxic conditions on hormonal and metabolic responses during sprint exercise. DESIGN: Seven male subjects participated in three experimental trials: 1) sprint exercise under normoxia (NSE); 2) sprint exercise under moderate normobaric hypoxia (16.4% oxygen) (HSE 16.4); and 3) sprint exercise under severe normobaric hypoxia (13.6% oxygen) (HSE 13.6). The sprint exercise consisted of four 30s all-out cycling bouts with 4-min rest between bouts. Glucose, free fatty acids (FFA), blood lactate, growth hormone (GH), epinephrine (E), norepinephrine (NE), and insulin concentrations in the HSE trials were measured before exposure to hypoxia (pre 1), 15 min after exposure to hypoxia (pre 2), and at 0, 15, 30, 60, 120, and 180 min after the exercise performed in hypoxia. The blood samples in the NSE trial were obtained in normoxia at the same time points as the HSE trials. RESULTS: Circulating levels of glucose, FFA, lactate, GH, E, NE, and insulin significantly increased after all three exercise trials (P < 0.05). The area under the curve (AUC) for GH was significantly higher in the HSE 13.6 trial than in the NSE and HSE 16.4 trials (P < 0.05). A maximal increase in FFA concentration was observed at 180 min after exercise and was not different between trials. CONCLUSION: These findings suggest that severe hypoxia may be an important factor for the enhancement of GH response to all-out sprint exercise.

Resistive exercises, with or without whole body vibration, prevent vertebral marrow fat accumulation during 60 days of head-down tilt bed rest in men

Fat accumulates in the bone marrow of lumbar vertebrae with bed rest. Exercise with or without whole body vibration may counter this effect. Our objectives were to measure 1) the vertebral fat fraction (VFF) of men subjected to bed rest who performed resistive exercises with (RVE, n = 7) or without whole body vibration(RE, n = 8) or no exercise (CTR, n = 9) using three MRI techniques; and 2) changes in peripheral blood counts. Twenty-four healthy men (age: 20-45 yr) underwent -6° head-down tilt (HDT) bed rest for 60 days. MRI was performed using three techniques (fat saturation, proton spectroscopy, and in and out of phase) to measure the fat fraction of L(3), L(4), and/or L(5) at baseline, mid-HDT, and end-HDT. Erythrocytes and leukocytes were counted at HDT days 19, 33, 47, 54, and 60. The mean absolute VFF was increased in the CTR group at mid-HDT and end-HDT (+3.9 ± 1.3 and +3.6 ± 1.2%, respectively, both P < 0.05). The RE group had a smaller VFF change than the CTR group at mid-HDT (-0.9 ± 1.2 vs. +3.9 ± 1.3%, P < 0.05). The RVE group had a smaller VFF change than the CTR group at end-HDT (-2.6 ± 1.9 vs. +3.5 ± 1.2%, P < 0.05). Erythrocyte counts were increased in all groups at HDT day 19 and HDT day 33 and in the RE group at HDT day 54 (all P < 0.05). Bed rest for 60 days at -6° HDT increased lumbar VFF in men beyond natural involution. RVE and RE regimens effectively prevented VFF accumulation. Higher erythrocyte counts were not altered by RVE or RE. Whole body vibration, along with RE administered to people with prolonged immobility, may prevent fat accumulation in their bone marrow.