Bingeing,Self‐restriction,and Increased Body Weight in Rats With Limited Access to a Sweet‐fat Diet

Objective: Prior research has shown that fasting alternated with a diet of standard rodent chow and a 10% sucrose solution produces bingeing on the sucrose, but animals remain at normal body weight. The present study investigated whether restricted access to a highly palatable combination of sugar and fat, without food deprivation, would instigate binge eating and also increase body weight. Methods and Procedures: Male rats were maintained for 25 days on one of four diets: (i) sweet‐fat chow for 2 h/day followed by ad libitum standard chow, (ii) 2‐h sweet‐fat chow only 3 days/week and access to standard chow the rest of the time, (iii) ad libitum sweet‐fat chow, or (iv) ad libitum standard chow. Results: Both groups with 2‐h access to the sweet‐fat chow exhibited bingeing behavior, as defined by excessively large meals. The body weight of these animals increased due to large meals and then decreased between binges as a result of self‐restricted intake of standard chow following binges. However, despite these fluctuations in body weight, the group with 2‐h access to sweet‐fat chow every day gained significantly more weight than the control group with standard chow available ad libitum. Discussion: These findings may have implications for the body weight fluctuations associated with binge‐eating disorder, as well as the relationship between binge eating and the obesity epidemic.     

High Prevalence of Methanobrevibacter smithii and Methanosphaera stadtmanae Detected in the Human Gut Using an Improved DNA Detection Protocol

Background

The low and variable prevalence of Methanobrevibacter smithii and Methanosphaera stadtmanae DNA in human stool contrasts with the paramount role of these methanogenic Archaea in digestion processes. We hypothesized that this contrast is a consequence of the inefficiencies of current protocols for archaeon DNA extraction. We developed a new protocol for the extraction and PCR-based detection of M. smithii and M. stadtmanae DNA in human stool.

Methodology/Principal Findings

Stool specimens collected from 700 individuals were filtered, mechanically lysed twice, and incubated overnight with proteinase K prior to DNA extraction using a commercial DNA extraction kit. Total DNA was used as a template for quantitative real-time PCR targeting M. smithii and M. stadtmanae 16S rRNA and rpoB genes. Amplification of 16S rRNA and rpoB yielded positive detection of M. smithii in 95.7% and M. stadtmanae in 29.4% of specimens. Sequencing of 16S rRNA gene PCR products from 30 randomly selected specimens (15 for M. smithii and 15 for M. stadtmanae) yielded a sequence similarity of 99–100% using the reference M. smithii ATCC 35061 and M. stadtmanae DSM 3091 sequences.

Conclusions/Significance

In contrast to previous reports, these data indicate a high prevalence of the methanogens M. smithii and M. stadtmanae in the human gut, with the former being an almost ubiquitous inhabitant of the intestinal microbiome.     

A Versatile Medium for Cultivating Methanogenic Archaea

Background

Methanobrevibacter smithii, Methanobrevibacter oralis, Methanosphaera stadtmanae, Methanomassilicoccus luminyensis and Methanobrevibacter arboriphilicus have been cultured from human digestive microbiota. Each one of these fastidious methanogenic archaea requires a specific medium for its growth, hampering their routine isolation and the culture.

Methodology/Principal Findings

A new culture medium here referred as SAB medium was optimized and tested to cultivate methanogens associated with human microbiota, as well as two mesophile methanogens Methanobacterium beijingense and Methanosaeta concilii. It was further tested for the isolation of archaea from 20 human stool specimens including 10 specimens testing positive for PCR detection of M. smithii. After inoculating 10⁵ colony-forming-unit archaea/mL or 1 g stool specimen in parallel in SAB medium and reference DSMZ medium in the presence of negative controls, growth of archaea was determined by optical microscopy and the measurement of methane production by gas chromatography. While the negative controls remained sterile, all tested archaea grew significantly more rapidly in SAB medium than in reference medium in 1–3 days (P<0.05, Student test). Among PCR-positive stool specimens, 10/10 grew in the SAB medium, 6/10 in DSMZ 119 medium, 5/10 in DSMZ 322 medium and 3/10 in DSMZ 334 c medium. Four out of ten PCR-negative stool specimens grew after a 3-week incubation in the SAB-medium whereas no growth was detected in any of the reference media. 16S rRNA gene sequencing yielded 99–100% sequence similarity with reference M. smithii except for one specimen that yielded 99–100% sequence similarity with reference Methanobrevibacter millerae.

Conclusions/Significance

SAB medium allows for the versatile isolation and growth of methanogenic archaea associated with human gut microbiota including the archaea missed by inoculation of reference media. Implementation of the SAB medium in veterinary and medical microbiology laboratories will ease the routine culture-based detection of methanogenic archaea in clinical and environmental specimens.     

Effects of increased meal frequency on fat oxidation and perceived hunger

Objective:

Consuming smaller, more frequent meals is often advocated as a means of controlling body weight, but studies demonstrating a mechanistic effect of this practice on factors associated with body weight regulation are lacking. The purpose of this study was to compare the effect of consuming three (3M) vs. six meals (6M) per day on 24‐h fat oxidation and subjective ratings of hunger.

Design and Methods:

Lean (body mass index <25 kg/m²) subjects (7M, 8F) were studied in a whole‐room calorimeter on two occasions in a randomized cross‐over design. Subjects were provided isoenergetic, energy balanced diets with a 1‐ to 2‐week washout between conditions. Hunger, fullness, and “desire to eat” ratings were assessed throughout the day using visual analog scales and quantified as area under the curve (AUC).

Results:

There were no differences (P < 0.05) in 24‐h energy expenditure (8.7 ± 0.3 vs. 8.6 ± 0.3 mj d^?1), 24‐h respiratory quotient (0.85 ± 0.01 vs. 0.85 ± 0.01), or 24‐h fat oxidation (82 ± 6 vs. 80 ± 7 g day^‐1) between 3M and 6M, respectively. There was no difference in fullness 24‐h AUC, but hunger AUC (41850 ± 2255 vs. 36612 ± 2556 mm.24 h, P = 0.03) and “desire to eat” AUC (47061 ± 1791 vs. 41170 ± 2574 mm.24 h, P = 0.03) were greater during 6M than 3M.

Conclusion:

We conclude that increasing meal frequency from three to six per day has no significant effect on 24‐h fat oxidation, but may increase hunger and the desire to eat.

     

Peroxisome proliferator‐activated receptor delta protects against obesity‐related glomerulopathy through the P38 MAPK pathway

Objective:

Obesity is a prominent component of metabolic syndrome and a major risk factor for renal disease. The aim of this study was to explore the effect of cross‐talk between peroxisome proliferator‐activated receptor (PPAR)δ and p38 mitogen‐activated protein kinase (p38 MAPK) on obesity‐related glomerulopathy.

Design and Methods:

Male Wistar rats were randomly assigned to standard laboratory chow or a high‐fat diet for 32 weeks. Glomerular mesangial cells HBZY‐1 and mature differentiation 3T3‐L1 cells were cocultured and were transfected with PPARδ‐expressing vectors or treated with agonist or inhibitor of PPARδ or p38 MAPK.

Results:

Rats on a high‐fat diet showed typical characteristics of metabolic syndrome including obesity, dyslipidemia, insulin resistance, and hypertension. Rats on a high‐fat diet also had significant glomerular hypertrophy and extracellular matrix accumulation, which were accompanied by increased p38 MAPK phosphorylation and decreased PPARδ expression in the kidney tissue. The roles of p38 MAPK and PPARδ in a coculture system of mesangial cells and mature differentiation 3T3‐L1 cells were further explored. PPARδ suppression promoted laminin and type IV collagen secretion through p38 MAPK phosphorylation in mesangial cells, whereas PPARδ overexpression or PPARδ agonist attenuated phosphorylation of p38 MAPK and laminin and type IV collagen secretion.

Conclusions:

The characteristics of obesity‐related glomerulopathy, which might be partly caused by PPARδ suppression‐induced p38 MAPK activation and laminin and type IV collagen secretion was demonstrated.     

Gestational and early life influences on infant body composition at 1 year

Excess weight gain during both pre‐ and postnatal life increases risk for obesity in later life. Although a number of gestational and early life contributors to this effect have been identified, there is a dearth of research to examine whether gestational factors and weight gain velocity in infancy exert independent effects on subsequent body composition and fat distribution.

Objective:

To test the hypothesis that birth weight, as a proxy of prenatal weight gain, and rate of weight gain before 6 months would be associated with total and truncal adiposity at 12 months of age.

Design and Methods:

Healthy, term infants (N = 47) were enrolled in the study and rate of weight gain (g/day) was assessed at 0‐3 months, 3‐6 months, and 6‐12 months.

Results:

Total and regional body composition were measured by dual‐energy X‐ray absorptiometry (DXA) at 12 months. Stepwise linear regression modeling indicated that lean mass at 12 months, after adjusting for child length, was predicted by rate of weight gain during each discrete period of infancy (P < 0.05), and by maternal pre‐pregnancy BMI (P < 0.05). Total fat mass at 12 months was predicted by rate of weight gain during each discrete period (P < 0.01), and by older maternal age at delivery (P < 0.05). Trunk fat mass at 12 months, after adjusting for leg fat mass, was predicted by rate of weight gain from 0‐3 months and 3‐6 months (P < 0.05).

Conclusion:

Results suggest that growth during early infancy may be a critical predictor of subsequent body composition and truncal fat distribution.     

The response of mycorrhizal colonization to elevated CO2 and climate change in Pascopyrum smithii and Bouteloua gracilis

Large intact soil cores of nearly pure stands of Pascopyrum smithii (western wheatgrass, C₃) and Bouteloua gracilis (blue grama, C₄) were extracted from the Central Plains Experimental Range in northeastern Colorado, USA and transferred to controlled environment chambers. Cores were exposed to a variety of water, temperature and CO₂ regimes for a total of four annual growth cycles. Root subsamples were harvested after the completion of the second and fourth growth cycles at a time corresponding to late winter, and were examined microscopically for the presence of mycorrhizae. After two growth cycles in the growth chambers, 54% of the root length was colonized in P. smithii, compared to 35% in blue grama. Field control plants had significantly lower colonization. Elevation of CO₂ increased mycorrhizal colonization in B. gracilis by 46% but had no effect in P. smithii. Temperatures 4° C higher than normal decreased colonization in P. smithii by 15%. Increased annual precipitation decreased colonization in both species. Simulated climate change conditions of elevated CO₂, elevated temperature and lowered precipitation decreased colonization in P. smithii but had less effect on B. gracilis. After four growth cycles in P. smithii, trends of treatments remained similar, but overall colonization rate decreased.     

A natural fiber complex reduces body weight in the overweight and obese: A double‐blind,randomized, placebo‐controlled study

Objective:

A proprietary natural fiber complex (Litramine IQP G‐002AS) derived from Opuntia ficus‐indica, and standardized on lipophilic activity, was previously shown in preclinical and human studies to reduce dietary fat absorption through gastrointestinal (GI) fat binding. Here, we investigated the efficacy and safety of IQP G‐002AS in body weight reduction.

Design and Methods:

One hundred twenty‐five overweight and obese adults participated in the study. Subjects were advised on physical activity, and received nutritional counseling, including hypocaloric diet plans (30% energy from fat and 500 kcal deficit/day). After a 2‐week placebo run‐in phase, subjects were randomized to receive either 3 g/day of IQP G‐002AS (IQ) or a placebo. The primary endpoint was change in body weight from baseline; secondary endpoints included additional obesity measures and safety parameters.

Results:

One hundred twenty‐three subjects completed the 12‐week treatment phase (intention‐to‐treat (ITT) population: 30 male and 93 female; mean BMI: 29.6 ± 2.8 kg/m² and age: 45.4 ± 11.3 years). The mean body weight change from baseline was 3.8 ± 1.8 kg in IQ vs. 1.4 ± 2.6 kg in placebo (P < 0.001). More IQ subjects lost at least 5% of their initial body weight compared to placebo (P = 0.027). Compared with placebo, IQ also showed significantly greater reduction in BMI, body fat composition, and waist circumference. IQ was well tolerated with no adverse reactions reported.

Conclusions:

These results suggest that the natural fiber complex Litramine IQP G‐002AS is effective in promoting weight loss.     

High‐fat Diet‐induced Ultradian Leptin and Insulin Hypersecretion are Absent in Obesity‐resistant Rats*

Objective: Sprague‐Dawley rats fed a high‐fat diet (HFD) are either obesity prone (OP) or obesity resistant (OR). We tested the hypothesis that differences in the ultradian rhythmic patterns of insulin and ghrelin in OP vs. OR rats promote obesity in OP rats. Research Methods and Procedures: Rats were fed regular chow or an HFD, and ultradian fluctuations in leptin, insulin, and ghrelin were analyzed in blood samples collected at 5‐minute intervals from intrajugular cannulae of freely moving rats. Results: Regular chow feeding resulted in a slow weight gain accompanied by small increases in insulin and leptin and a decrease in ghrelin discharge, with only the pulse amplitude significantly altered. Similar changes were observed in OR rats, despite HFD consumption. In contrast, OP rats exhibited a high rate of weight gain and marked hyperinsulinemia, hyperleptinemia, and hypoghrelinemia; amplitude was altered, but frequency was stable. In a short‐term experiment, HFD elicited similar secretory patterns of smaller magnitude even in the absence of weight gain. Discussion: We showed that three hormonal signals of disparate origin involved in energy homeostasis were secreted in discrete episodes, and only the pulse amplitude component was vulnerable to age and HFD consumption. Increases in insulin and leptin and decreases in ghrelin pulse amplitude caused by HFD were exaggerated in OP rats relative to OR rats and preceded the weight increase. These findings show that a distinct genetic predisposition in the endocrine organs of OR rats confers protection against high‐fat intake‐induced ultradian hypersecretion of obesity‐promoting hormonal signals.     

Adipose Tissue Dysfunction Occurs Independently of Obesity in Adipocyte‐Specific Oncostatin Receptor Knockout Mice

Objective

This study examined the phenotypic effects of adipocyte‐specific oncostatin M receptor (OSMR) loss in chow‐fed mice.

Methods

Chow‐fed adipocyte‐specific OSMR knockout (FKO) mice and littermate OSMR^fl/fl controls were studied. Tissue weights, insulin sensitivity, adipokine production, and stromal cell immunophenotypes were assessed in epididymal fat (eWAT); serum adipokine production was also assessed. In vitro, adipocytes were treated with oncostatin M, and adipokine gene expression was assessed.

Results

Body weights, fasting blood glucose levels, and eWAT weights did not differ between genotypes. However, the eWAT of OSMR^FKO mice was modestly less responsive to insulin stimulation than that of OSMR^fl/fl mice. Notably, significant increases in adipokines, including C‐reactive protein, lipocalin 2, intercellular adhesion molecule‐1, and insulinlike growth factor binding protein 6, were observed in the eWAT of OSMR^FKO mice. In addition, significant increases in fetuin A and intercellular adhesion molecule‐1 were detected in OSMR^FKO serum. Flow cytometry revealed a significant increase in leukocyte number and modest, but not statistically significant, increases in B cells and T cells in the eWAT of OSMR^FKO mice.

Conclusions

The chow‐fed OSMR^FKO mice exhibited adipose tissue dysfunction and increased proinflammatory adipokine production. These results suggest that intact adipocyte oncostatin M–OSMR signaling is necessary for adipose tissue immune cell homeostasis.

     

Dietary Fat Dose Dependently Increases Spontaneous Caloric Intake in Rat

Objective: To characterize the dose‐response relationship between dietary fat to carbohydrate ratio and spontaneous caloric intake. Research Methods and Procedures: Male Long‐Evans rats consumed milk‐based liquid diets that differed in fat content (17% to 60% of kilocalories) but had equivalent protein content and energy density. In Experiment 1, rats consumed one of the diets (n = 9/diet group) as the sole source of nutrition for 16 days. In Experiment 2, diets were offered as an option to nutritionally complete chow for 4 days followed by a 3‐day chow‐only washout in a randomized within‐subjects design (n = 30). In Experiment 3, nine rats received isocaloric intragastric infusions of diet overnight, with chow available ad libitum. At least two no‐infusion days separated the different diet infusions, which were given in random order. Food intake was measured daily Results: Dietary fat dose dependently increased total daily kilocalories in each of the three paradigms. Discussion: These data imply that the postingestive effects of carbohydrate and fat differentially engage the physiological substrates that regulate daily caloric intake. These findings reiterate the importance of investigating macronutrient‐specific controls of feeding, rather than prematurely concluding that dietary attributes that covary with fat content (e.g., caloric density and palatability) drive the overeating associated with a high‐fat diet.     

Maternal High‐Fat Diet Effects on Adaptations to Metabolic Challenges in Male and Female Juvenile Nonhuman Primates

Objective

This study aimed to determine whether maternal high‐fat diet (HFD) consumption in nonhuman primates alters the ability of offspring to adapt metabolically to nutrient and caloric challenges.

Methods

Offspring from Japanese macaque dams fed either a control (CTR) diet or HFD were weaned onto a CTR diet creating two groups: maternal HFD (mHFD, n = 18) and maternal CTR (mCTR) diet (n = 12). Male and female offspring were exposed to a 5‐day 30% calorie restriction and to a 35‐day HFD challenge (HFDC), at 16 and 24 months of age, respectively. Caloric intake, body weight, and energy expenditure were measured.

Results

Offspring from both groups showed similar body weight, food intake, and metabolic adaptations to a 5‐day calorie restriction. mHFD offspring demonstrated increased food intake and early weight gain in response to a 35‐day HFDC; however, group differences in weight dissipated during the challenge. Unlike mCTR animals, the mHFD group had a significant increase in fasting insulin after acute HFD exposure.

Conclusions

The current findings indicate that offspring exposed to an mHFD show metabolic adaptations to calorie restriction that are largely similar to those of offspring exposed to a mCTR diet but show delayed adaptation upon exposure to an acute HFDC.

     

Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans

Objective:

To assess how intrahepatic fat and insulin resistance relate to daily fructose and energy intake during short‐term overfeeding in healthy subjects.

Design and methods:

The analysis of the data collected in several studies in which fasting hepatic glucose production (HGP), hepatic insulin sensitivity index (HISI), and intrahepatocellular lipids (IHCL) had been measured after both 6‐7 days on a weight‐maintenance diet (control, C; n = 55) and 6‐7 days of overfeeding with 1.5 (F1.5, n = 7), 3 (F3, n = 17), or 4 g fructose/kg/day (F4, n = 10), with 3 g glucose/kg/day (G3, n = 11), or with 30% excess energy as saturated fat (fat30%, n = 10).

Results:

F3, F4, G3, and fat30% all significantly increased IHCL, respectively by 113 ± 86, 102 ± 115, 59 ± 92, and 90 ± 74% as compared to C (all P < 0.05). F4 and G3 increased HGP by 16 ± 10 and 8 ± 11% (both P < 0.05), and F3 and F4 significantly decreased HISI by 20 ± 22 and 19 ± 14% (both P < 0.01). In contrast, there was no significant effect of fat30% on HGP or HISI.

Conclusions:

Short‐term overfeeding with fructose or glucose decreases hepatic insulin sensitivity and increases hepatic fat content. This indicates short‐term regulation of hepatic glucose metabolism by simple carbohydrates.     

Altered Feeding Patterns in Rats Exposed to a Palatable Cafeteria Diet: Increased Snacking and Its Implications for Development of Obesity

Background

Rats prefer energy-rich foods over chow and eat them to excess. The pattern of eating elicited by this diet is unknown. We used the behavioral satiety sequence to classify an eating bout as a meal or snack and compared the eating patterns of rats fed an energy rich cafeteria diet or chow.

Methods

Eight week old male Sprague Dawley rats were exposed to lab chow or an energy-rich cafeteria diet (plus chow) for 16 weeks. After 5, 10 and 15 weeks, home-cage overnight feeding behavior was recorded. Eating followed by grooming then resting or sleeping was classified as a meal; whereas eating not followed by the full sequence was classified as a snack. Numbers of meals and snacks, their duration, and waiting times between feeding bouts were compared between the two conditions.

Results

Cafeteria-fed rats ate more protein, fat and carbohydrate, consistently ingesting double the energy of chow-fed rats, and were significantly heavier by week 4. Cafeteria-fed rats tended to take multiple snacks between meals and ate fewer meals than chow-fed rats. They also ate more snacks at 5 weeks, were less effective at compensating for snacking by reducing meals, and the number of snacks in the majority of the cafeteria-fed rats was positively related to terminal body weights.

Conclusions

Exposure to a palatable diet had long-term effects on feeding patterns. Rats became overweight because they initially ate more frequently and ultimately ate more of foods with higher energy density. The early increased snacking in young cafeteria-fed rats may represent the establishment of eating habits that promote weight gain.     

Efficiency of intermittent exercise on adiposity and fatty liver in rats fed with high-fat diet

Objective: This study aimed to examine and compare the effects of continuous or intermittent exercises on adiposity and fatty liver in rats fed with high‐fat diet. Methods and Procedures: Wistar rats were divided according to diet composition—chow diet (C) or high‐fat diet (H)—and kinds of exercise—sedentary (S), continuous (CE), or intermittent (IE) exercises. The CE group swam 90 min/day, and the IE group swam 3 × 30 min/day (at 4‐h intervals between sessions); both groups exercised 5 days/week during 8 weeks. Body weight and food intake were recorded daily. Lipogenesis rate in vivo was determined by the incorporation of ³H₂O into saponified lipids in retroperitoneal (RET), epididymal (EPI), and visceral (VIS) white adipose tissues, brown adipose tissue (BAT), liver (L), and gastrocnemius muscle (GAST) using the gravimetric method. Total cholesterol, high‐density lipoprotein (HDL)‐cholesterol, and triacylglycerol (TG) were analyzed. Results: The major finding of this study is that IE was more efficient than CE in reducing the adverse effects of high‐fat diet and sedentarism. There was an improvement in the lipid profile and a reduction in food intake, body weight gain, visceral and central adiposity, and fatty liver, contributing to the control of obesity and other comorbidities, including nonalcoholic fat liver diseases. Discussion: Earlier studies have discussed the effects of diet consumption on adiposity and their relation to chronic diseases and obesity. This study discusses the effects of high‐fat diet consumption and the different kinds of exercise on weight gain, adiposity, fatty liver, and lipid profile in rats. The results may depend on the exercise, time of each session, age, gender, and experimental period.     

A dairy‐based high calcium diet improves glucose homeostasis and reduces steatosis in the context of preexisting obesity

Objective:

High dietary calcium (Ca) in the context of a dairy food matrix has been shown to reduce obesity development and associated inflammation in diet‐induced obese (DIO) rodents. The influence of Ca and dairy on these phenotypes in the context of preexisting obesity is not known. Furthermore, interpretations have been confounded historically by differences in body weight gain among DIO animals fed dairy‐based protein or high Ca.

Design and Methods:

Adiposity along with associated metabolic and inflammatory outcomes were measured in DIO mice previously fattened for 12 week on a soy protein‐based obesogenic high fat diet (45% energy, 0.5% adequate Ca), then fed one of three high fat diets (n = 29‐30/group) for an additional 8 week: control (same as lead‐in diet), high‐Ca (1.5% Ca), or high‐Ca + nonfat dry milk (NFDM).

Results and Conclusion:

Mice fed high‐Ca + NFDM had modestly, but significantly, attenuated weight gain compared to mice fed high‐Ca or versus controls (P < 0.001), whereas mice fed high‐Ca alone had increased weight gain compared to controls (P < 0.001). Total measured adipose depot weights between groups were similar, as were white adipose tissue inflammation and macrophage infiltration markers (e.g. TNFα, IL‐6, CD68 mRNAs). Mice fed high‐Ca + NFDM had significantly improved glucose tolerance following a glucose tolerance test, and markedly lower liver triglycerides compared to high‐Ca and control groups. Improved metabolic phenotypes in prefattened DIO mice following provision of a diet enriched with dairy‐based protein and carbohydrates appeared to be driven by non‐Ca components of dairy and were observed despite minimal differences in body weight or adiposity.     

Pioglitazone retrieves hepatic antioxidant DNA repair in a mice model of high fat diet

Background  

Pioglitazone was reported to improve hepatic steatosis and necroinflammation in human studies. To investigate whether the hepato-protective effect of pioglitazone was associated with an improvement of antioxidant defense mechanism, oxidative DNA damage and repair activity were determined in a high fat diet model. Male C57BL/6 mice were respectively fed with a 30% fat diet, the same diet with pioglitazone 100 mg/kg/day, or a chow diet as control for 8 weeks. Tissue oxidative stress was indicated by malondialdehyde concentration. Oxidative DNA damage was detected by immunohistochemical 8-oxoG staining. Enzymatic antioxidant defense was detected by the real-time PCR of superoxide dismutase (Sod1, Sod2) and DNA glycosylase (Ogg1, MutY). Oxidative DNA repair was detected by immunohistochemical staining and western blotting of OGG1 expression.     

Absence of Diabetes and Pancreatic Exocrine Dysfunction in a Transgenic Model of Carboxyl-Ester Lipase-MODY (Maturity-Onset Diabetes of the Young)

Background

CEL-MODY is a monogenic form of diabetes with exocrine pancreatic insufficiency caused by mutations in CARBOXYL-ESTER LIPASE (CEL). The pathogenic processes underlying CEL-MODY are poorly understood, and the global knockout mouse model of the CEL gene (CELKO) did not recapitulate the disease. We therefore aimed to create and phenotype a mouse model specifically over-expressing mutated CEL in the pancreas.

Methods

We established a monotransgenic floxed (flanking LOX sequences) mouse line carrying the human CEL mutation c.1686delT and crossed it with an elastase-Cre mouse to derive a bitransgenic mouse line with pancreas-specific over-expression of CEL carrying this disease-associated mutation (TgCEL). Following confirmation of murine pancreatic expression of the human transgene by real-time quantitative PCR, we phenotyped the mouse model fed a normal chow and compared it with mice fed a 60% high fat diet (HFD) as well as the effects of short-term and long-term cerulein exposure.

Results

Pancreatic exocrine function was normal in TgCEL mice on normal chow as assessed by serum lipid and lipid-soluble vitamin levels, fecal elastase and fecal fat absorption, and the normoglycemic mice exhibited normal pancreatic morphology. On 60% HFD, the mice gained weight to the same extent as controls, had normal pancreatic exocrine function and comparable glucose tolerance even after resuming normal diet and follow up up to 22 months of age. The cerulein-exposed TgCEL mice gained weight and remained glucose tolerant, and there were no detectable mutation-specific differences in serum amylase, islet hormones or the extent of pancreatic tissue inflammation.

Conclusions

In this murine model of human CEL-MODY diabetes, we did not detect mutation-specific endocrine or exocrine pancreatic phenotypes, in response to altered diets or exposure to cerulein.     

Metformin modifies the exercise training effects on risk factors for cardiovascular disease in impaired glucose tolerant adults

Impaired glucose tolerant (IGT) adults are at elevated risk for cardiovascular disease (CVD). Exercise or metformin reduce CVD risk, but the efficacy of combining treatments is unclear.

Objective:

To determine the effects of exercise training plus metformin (EM), compared with each treatment alone, on CVD risk factors in IGT adults.

Design and Methods:

Subjects were assigned to placebo (P), metformin (M), exercise training plus placebo (EP), or EM (8/group). In a double‐blind design, P or 2,000 mg/d of M were administered for 12 weeks and half performed aerobic and resistance training 3 days/week for ～60 min/day at 70% pretraining heart rate peak. Outcomes included adiposity, blood pressure (BP), lipids, and high sensitivity C‐reactive protein (hs‐CRP). Z‐scores were calculated to determine metabolic syndrome severity.

Results:

M and EM, but not EP, decreased body weight compared with P (P < 0.05). M and EP lowered systolic blood pressure by 6% (P < 0.05), diastolic blood pressure by 6% (P < 0.05), and hs‐CRP by 20% (M: trend P = 0.06; EP: P < 0.05) compared with P. Treatments raised high‐density lipoprotein cholesterol (P < 0.05; EM: trend P = 0.06) compared with P and lowered triacyglycerol (P < 0.05) and metabolic syndrome Z‐score compared with baseline (EP; trend P = 0.07 and EM or M; P < 0.05).

Conclusions:

Although exercise and/or metformin improve some CVD risk factors, only training or metformin alone lowered hs‐CRP and BP. Thus, metformin may attenuate the effects of training on some CVD risk factors and metabolic syndrome severity in IGT adults.