Associations between protein to non-protein ratio and intakes of other dietary components in a cohort aged 65-75 years: the Nutrition for Healthy Living Study.

OBJECTIVE: Diets with a low proportion of energy from protein have shown to cause overconsumption of non-protein energy, known as Protein Leverage. Older adults are susceptible to nutritional inadequacy. The aim was to investigate associations between protein to non-protein ratio (P:NP) and intakes of dietary components and assess the nutritional adequacy of individuals aged 65-75 years from the Nutrition for Healthy Living (NHL) Study. DESIGN: Cross-sectional. Nutritional intakes from seven-day weighed food records were compared with the Nutrient Reference Values for Australia and New Zealand, Australian Guide to Healthy Eating, Australian Dietary Guidelines and World Health Organisation Free Sugar Guidelines. Associations between P:NP and intakes of dietary components were assessed through linear regression analyses. SETTING: NHL Study. PARTICIPANTS: 113 participants. RESULTS: Eighty-eight (59 female and 29 male) with plausible dietary data had a median (interquartile range) age of 69 years (67-71), high education level (86 %) and sources of income apart from the age pension (81 %). Substantial proportions had intakes below recommendations for dairy and alternatives (89 %), wholegrain (89 %) and simultaneously exceeded recommendations for discretionary foods (100 %) and saturated fat (92 %). In adjusted analyses, P:NP (per 1 % increment) was associated with lower intakes of energy, saturated fat, free sugar and discretionary foods and higher intakes of vitamin B12, Zn, meat and alternatives, red meat, poultry and wholegrain % (all P < 0·05). CONCLUSIONS: Higher P:NP was associated with lower intakes of energy, saturated fat, free sugar and discretionary. Our study revealed substantial nutritional inadequacy in this group of higher socio-economic individuals aged 65-75 years.

A randomized clinical trial to investigate the effect of dietary protein sources on periodontal health.

AIM: The aim was to assess two macronutrient interventions in a 2 × 2 factorial dietary design to determine their effects on oral health. MATERIALS AND METHODS: Participants (65-75 years old) with a body mass index between 20 and 35 kg/m2 of a larger randomized control trial who consented to an oral health assessment were recruited. They had ad libitum access to one of four experimental diets (omnivorous higher fat or higher carbohydrate, semi-vegetarian higher fat or higher carbohydrate) for 4 weeks. The periodontal examination included periodontal probing depth (PPD), clinical attachment level (CAL), and bleeding on probing. Oral plaque and gingival crevicular fluid (GCF) were collected before and after the intervention. RESULTS: Between baseline and follow up, the number of sites with a CAL <5 mm (mean difference [MD] -5.11 ± 9.68, p = .039) increased and the GCF amount (MD -23.42 ± 39.42 Periotron Units [PU], p = .050) decreased for the semi-vegetarian high-fat diet. For the mean proportion of sites with PPD reduction of >1 mm and CAL gain of >1 mm, significant differences were calculated between the diets investigated. The clinical parameters were not associated with changes in the oral microbiota. CONCLUSIONS: The results of this study provided evidence that a semi-vegetarian high-fat diet provides benefits to clinical parameters of periodontal health. This study is registered in ClinicalTrials.gov (ACTRN12616001606471).

Diet quality and its implications on the cardio-metabolic, physical and general health of older men: the Concord Health and Ageing in Men Project (CHAMP).

The revised Dietary Guideline Index (DGI-2013) scores individuals' diets according to their compliance with the Australian Dietary Guideline (ADG). This cross-sectional study assesses the diet quality of 794 community-dwelling men aged 74 years and older, living in Sydney, Australia participating in the Concord Health and Ageing in Men Project; it also examines sociodemographic and lifestyle factors associated with DGI-2013 scores; it studies associations between DGI-2103 scores and the following measures: homoeostasis model assessment - insulin resistance, LDL-cholesterol, HDL-cholesterol, TAG, blood pressure, waist:hip ratio, BMI, number of co-morbidities and medications and frailty status while also accounting for the effect of ethnicity in these relationships. Median DGI-2013 score was 93·7 (54·4, 121·2); most individuals failed to meet recommendations for vegetables, dairy products and alternatives, added sugar, unsaturated fat and SFA, fluid and discretionary foods. Lower education, income, physical activity levels and smoking were associated with low scores. After adjustments for confounders, high DGI-2013 scores were associated with lower HDL-cholesterol, lower waist:hip ratios and lower probability of being frail. Proxies of good health (fewer co-morbidities and medications) were not associated with better compliance to the ADG. However, in participants with a Mediterranean background, low DGI-2013 scores were not generally associated with poorer health. Older men demonstrated poor diet quality as assessed by the DGI-2013, and the association between dietary guidelines and health measures and indices may be influenced by ethnic background.

Nutritional ecology of obesity: from humans to companion animals.

We apply nutritional geometry, a framework for modelling the interactive effects of nutrients on animals, to help understand the role of modern environments in the obesity pandemic. Evidence suggests that humans regulate the intake of protein energy (PE) more strongly than non-protein energy (nPE), and consequently will over- and under-ingest nPE on diets with low or high PE, respectively. This pattern of macronutrient regulation has led to the protein leverage hypothesis, which proposes that the rise in obesity has been caused partly by a shift towards diets with reduced PE:nPE ratios relative to the set point for protein regulation. We discuss potential causes of this mismatch, including environmentally induced reductions in the protein density of the human diet and factors that might increase the regulatory set point for protein and hence exacerbate protein leverage. Economics--the high price of protein compared with fats and carbohydrates--is one factor that might contribute to the reduction of dietary protein concentrations. The possibility that rising atmospheric CO2 levels could also play a role through reducing the PE:nPE ratios in plants and animals in the human food chain is discussed. Factors that reduce protein efficiency, for example by increasing the use of ingested amino acids in energy metabolism (hepatic gluconeogenesis), are highlighted as potential drivers of increased set points for protein regulation. We recommend that a similar approach is taken to understand the rise of obesity in other species, and identify some key gaps in the understanding of nutrient regulation in companion animals.

Rapid benefits in older age from transition to whole food diet regardless of protein source or fat to carbohydrate ratio: Arandomised control trial.

Plant-based diets reduces the risk of chronic conditions. The interaction between protein source and other macronutrients-fat (F) and carbohydrate (C)-has yet to be investigated. The aim was to assess the main and interactive effects of protein-source (plant vs. animal) and F:C (high or low) and the transition from an Australian diet to a whole food diet on various health markers in older individuals. This single-blinded, parallel, randomised experimental trial used a 2 × 2 factorial design to compare pro-vegetarian (70:30 plant to animal) versus omnivorous (50:50 plant to animal) diets at 14% protein and varying fat-to-carbohydrate ratios (high fat ~40% vs. low fat ~30%) over 4 weeks. Study foods were provided, alcohol consumption was discouraged, and dietary intake was determined through food records. Analysis included both RCT and observational data. Changes in appetite, palatability of diets, and dietary intake were assessed. Body composition, muscle strength, function, gut microbiome, and cardiometabolic health parameters were measured. Data from 113 (of the 128 randomised) individuals aged 65-75 years were analysed. Pro-vegetarian diets reduced diastolic blood pressure, total cholesterol and glucose levels. Moreover, the overall sample exhibited increased short-chain fatty acids and FGF21 levels, as well as improvements in body composition, function, and cardio-metabolic parameters irrespective of dietary treatment. Transitioning to a diet rich in fruit, vegetables, fibre, and moderate protein was associated with improved health markers in older age, with added benefits from pro-vegetarian diets. Further research on long-term effects is needed.

Design and testing of foods differing in protein to energy ratios.

Our aim was to design a selection of foods with differing proportions of protein but equal palatability in two settings, Sydney Australia and Kingston Jamaica. The foods were manipulated to contain 10, 15 or 25% E as protein with reciprocal changes in carbohydrate to 60, 55 or 45% E and dietary fat was kept constant at 30%. Naïve participants did not identify a difference in protein between the versions. On average, the versions were rated equal in pleasantness (Sydney-10%: 44±2, 15%: 49±2 and 25%: 49±2 Kingston-10%: 41±3, 15%: 41±3 and 25%: 37±3).

Postnatal nutrition alters body composition in adult offspring exposed to maternal protein restriction.

The insulin-like growth factor (IGF) system is altered with intra-uterine growth retardation and in adult metabolic disease. The aim of the present study was to observe effects of continued protein restriction on the IGF-I system and body composition in offspring of mothers fed a low-protein (LP) diet. Offspring from Wistar dams fed either a 20 % (CON) or 8 % (LP) protein diet during gestation and lactation were studied at birth, 10 d, weaning and at 12 weeks after maintenance on either the 8 % (lp) or 20 % (con) protein diet from weaning. LP offspring had reduced weaning weights (P < 0.05) and reduced serum insulin (P < 0.005). Serum IGF-I (P < 0.001) and acid-labile subunit (ALS) (P < 0.0001) were reduced at 10 and 21 d. Hepatic expression of IGF-I (P < 0.05) and ALS (P < 0.005) were reduced at 10 and 21 d. IGF binding protein (IGFBP)-1 hepatic expression was elevated at 10 d (P < 0.001) but not at 21 d. Adult LP-con offspring had reduced body weight (P < 0.05), lean (P < 0.0001) and bone (P < 0.0001) but not fat (P = 0.6) mass with no persistent effects on IGF-I, ALS and IGFBP-1.Postnatal lp feeding reduced lean mass (P < 0.0001) and bone mass (P < 0.0001) in CON and LP animals. Percentage fat (LP P = 0.04; CON P = 0.6) and IGFBP-1 (LP P = 0.01; CON P = 0.2) were increased in LP-lp but not CON-lp offspring. This suggests that postnatal nutrition is important in the effects of maternal protein restriction on adult body composition and that IGFBP-1 may be involved.

Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states.

Berberine has been shown to have antidiabetic properties, although its mode of action is not known. Here, we have investigated the metabolic effects of berberine in two animal models of insulin resistance and in insulin-responsive cell lines. Berberine reduced body weight and caused a significant improvement in glucose tolerance without altering food intake in db/db mice. Similarly, berberine reduced body weight and plasma triglycerides and improved insulin action in high-fat-fed Wistar rats. Berberine downregulated the expression of genes involved in lipogenesis and upregulated those involved in energy expenditure in adipose tissue and muscle. Berberine treatment resulted in increased AMP-activated protein kinase (AMPK) activity in 3T3-L1 adipocytes and L6 myotubes, increased GLUT4 translocation in L6 cells in a phosphatidylinositol 3' kinase-independent manner, and reduced lipid accumulation in 3T3-L1 adipocytes. These findings suggest that berberine displays beneficial effects in the treatment of diabetes and obesity at least in part via stimulation of AMPK activity.

Meta-analysis of variance: an illustration comparing the effects of two dietary interventions on variability in weight.

Meta-analysis, which drives evidence-based practice, typically focuses on the average response of subjects to a treatment. For instance in nutritional research the difference in average weight of participants on different diets is typically used to draw conclusions about the relative efficacy of interventions. As a result of their focus on the mean, meta-analyses largely overlook the effects of treatments on inter-subject variability. Recent tools from the study of biological evolution, where inter-individual variability is one of the key ingredients for evolution by natural selection, now allow us to study inter-subject variability using established meta-analytic models. Here we use meta-analysis to study how low carbohydrate (LC) ad libitum diets and calorie restricted diets affect variance in mass. We find that LC ad libitum diets may have a more variable outcome than diets that prescribe a reduced calorie intake. Our results suggest that whilst LC diets are effective in a large proportion of the population, for a subset of individuals, calorie restricted diets may be more effective. There is evidence that LC ad libitum diets rely on appetite suppression to drive weight loss. Extending this hypothesis, we suggest that between-individual variability in protein appetite may drive the trends that we report. A priori identification of an individual's target intake for protein may help define the most effective dietary intervention to prescribe for weight loss.

Developmental contributions to macronutrient selection: a randomized controlled trial in adult survivors of malnutrition.

BACKGROUND AND OBJECTIVES: Birthweight differences between kwashiorkor and marasmus suggest that intrauterine factors influence the development of these syndromes of malnutrition and may modulate risk of obesity through dietary intake. We tested the hypotheses that the target protein intake in adulthood is associated with birthweight, and that protein leveraging to maintain this target protein intake would influence energy intake (EI) and body weight in adult survivors of malnutrition. METHODOLOGY: Sixty-three adult survivors of marasmus and kwashiorkor could freely compose a diet from foods containing 10, 15 and 25 percentage energy from protein (percentage of energy derived from protein (PEP); Phase 1) for 3 days. Participants were then randomized in Phase 2 (5 days) to diets with PEP fixed at 10%, 15% or 25%. RESULTS: Self-selected PEP was similar in both groups. In the groups combined, selected PEP was 14.7, which differed significantly (P < 0.0001) from the null expectation (16.7%) of no selection. Self-selected PEP was inversely related to birthweight, the effect disappearing after adjusting for sex and current body weight. In Phase 2, PEP correlated inversely with EI (P = 0.002) and weight change from Phase 1 to 2 (P = 0.002). Protein intake increased with increasing PEP, but to a lesser extent than energy increased with decreasing PEP. CONCLUSIONS AND IMPLICATIONS: Macronutrient intakes were not independently related to birthweight or diagnosis. In a free-choice situation (Phase 1), subjects selected a dietary PEP significantly lower than random. Lower PEP diets induce increased energy and decreased protein intake, and are associated with weight gain.

Raised FGF-21 and Triglycerides Accompany Increased Energy Intake Driven by Protein Leverage in Lean, Healthy Individuals: A Randomised Trial.

A dominant appetite for protein drives increased energy intake in humans when the proportion of protein in the diet is reduced down to approximately 10% of total energy. Compensatory feeding for protein is apparent over a 1­2 d period but the mechanisms driving this regulation are not fully understood. Fibroblast growth factor-21 (FGF-21) has been identified as a candidate protein signal as levels increase in the circulation when dietary protein is low. The aim of this randomised controlled trial was to assess whether changes in percent dietary protein over a 4 d ad libitum experimental period in lean, healthy participants influenced energy intake, metabolic health, circulating FGF-21 and appetite regulating hormones including ghrelin, glucagon like peptide-1 and cholecystokinin. Twenty-two lean, healthy participants were fed ad libitum diets containing 10, 15 and 25% protein, over three, 4 d controlled, in-house experimental periods. Reduced dietary protein intake from 25% to 10% over a period of 4 d was associated with 14% increased energy intake (p = 0.02) as previously reported, and a 6-fold increase in fasting circulating plasma FGF-21 levels (p<0.0001), a 1.5-fold increase in serum triglycerides (p<0.0001), and a 0.9-fold decrease in serum total cholesterol (p = 0.02). Serum HDL cholesterol was reduced with a reduction in dietary protein from 15% to 10% (p = 0.01) over 4 d but not from 25% to 10% (p = 0.1) and the change from baseline was not different between diets. Plasma fasting insulin levels following the 4 d study period were significantly lower following the 25% ad libitum study period compared to the 15% protein period (p = 0.014) but not the 10% protein period (p = 0.2). Variability in interstitial glucose during each study period increased with a decrease in dietary protein from 25% to 15% and 10% (p = 0.001 and p = 0.04, respectively). Ghrelin, glucagon-like peptide-1 and cholecystokinin were unchanged. Increases in energy intake, plasma FGF-21 and serum triglycerides were associated with reductions in percent dietary protein from 25% to 10% energy over a 4 d ad libitum in-house feeding period and may be important in regulation of dietary protein intake. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12616000144415.

Effects of dietary protein to carbohydrate balance on energy intake, fat storage, and heat production in mice.

OBJECTIVE: Protein leverage plays a role in driving increased energy intakes that may promote weight gain. The influence of the protein to carbohydrate ratio (P:C) in diets of C57BL/6J mice on total energy intake, fat storage, and thermogenesis was investigated. DESIGN AND METHODS: Male mice (9 weeks old) were provided ad libitum access to one of five isocaloric diets that differed in P:C. Food intake was recorded for 12 weeks. After 16 weeks, white adipose tissue (WAT) and brown adipose tissue (BAT) deposits were dissected, weighed, and the expression levels of key metabolic regulators were determined in BAT. In a separate cohort, body surface temperature was measured in response to 25 diets differing in protein, fat, and carbohydrate content. RESULTS: Mice on low P:C diets (9:72 and 17:64) had greater total energy intake and increased WAT and BAT stores. Body surface temperature increased with total energy intake and with protein, fat, and carbohydrate, making similar contributions per kJ ingested. Expression of three key regulators of thermogenesis were downregulated in BAT in mice on the lowest P:C diet. CONCLUSIONS: Low-protein diets induced sustained hyperphagia and a generalized expansion of fat stores. Increased body surface temperature on low P:C diets was consistent with diet-induced thermogenesis (DIT) as a means to dissipate excess ingested energy on such diets, although this was not sufficient to prevent development of increased adiposity. Whether BAT was involved in DIT is not clear. Increased BAT mass on low P:C diets might suggest so, but patterns of thermogenic gene expression do not support a role for BAT in DIT, although they might reflect failure of thermogenic function with prolonged exposure to a low P:C diet.

Testing protein leverage in lean humans: a randomised controlled experimental study.

A significant contributor to the rising rates of human obesity is an increase in energy intake. The 'protein leverage hypothesis' proposes that a dominant appetite for protein in conjunction with a decline in the ratio of protein to fat and carbohydrate in the diet drives excess energy intake and could therefore promote the development of obesity. Our aim was to test the 'protein leverage hypothesis' in lean humans by disguising the macronutrient composition of foods offered to subjects under ad libitum feeding conditions. Energy intakes and hunger ratings were measured for 22 lean subjects studied over three 4-day periods of in-house dietary manipulation. Subjects were restricted to fixed menus in random order comprising 28 foods designed to be similar in palatability, availability, variety and sensory quality and providing 10%, 15% or 25% energy as protein. Nutrient and energy intake was calculated as the product of the amount of each food eaten and its composition. Lowering the percent protein of the diet from 15% to 10% resulted in higher (+12±4.5%, p = 0.02) total energy intake, predominantly from savoury-flavoured foods available between meals. This increased energy intake was not sufficient to maintain protein intake constant, indicating that protein leverage is incomplete. Urinary urea on the 10% and 15% protein diets did not differ statistically, nor did they differ from habitual values prior to the study. In contrast, increasing protein from 15% to 25% did not alter energy intake. On the fourth day of the trial, however, there was a greater increase in the hunger score between 1-2 h after the 10% protein breakfast versus the 25% protein breakfast (1.6±0.4 vs 25%: 0.5±0.3, p = 0.005). In our study population a change in the nutritional environment that dilutes dietary protein with carbohydrate and fat promotes overconsumption, enhancing the risk for potential weight gain.

Elevated insulin sensitivity in low-protein offspring rats is prevented by a high-fat diet and is associated with visceral fat.

This study tests the hypothesis that a high-fat postnatal diet increases fat mass and reduces improved insulin sensitivity (IS) found in the low-protein model of maternal undernutrition. Offspring from Wistar dams fed either a 20% (control (CON)) or 8% (low protein (LP)) protein diet during gestation and lactation were randomly assigned to a control (con) or cafeteria (caf) diet at weaning (21 days) until 3 months of age at which point IS was measured (hyperinsulinemic-euglycemic clamp). Fat mass, growth, energy intake (EI) and expenditure (EE), fuel utilization, insulin secretion, and leptin and adiponectin levels were measured to identify a possible role in any changes in IS. IS was increased in LP-con in comparison to CON-con animals. Cafeteria feeding prevented this increase in LP animals but had no effect in CON animals (insulin-stimulated glucose infusion rates (GIRs; mg/min/kg); CON-con: 13.9 +/- 1.0, CON caf: 12.1 +/- 2.1, LP-con: 25.4 +/- 2.0, LP-caf: 13.7 +/- 3.7, P < 0.05). CON-caf animals had similar percent epididymal white adipose tissue (%EWAT; CON-con: 1.71 +/- 0.09 vs. CON-caf: 1.66 +/- 0.08) and adiponectin (microg/ml: CON-con: 4.61 +/- 0.34 vs. CON-caf: 3.67 +/- 0.18) except hyperinsulinemia and relative hyperleptinemia in comparison to CON-con. Differently, LP-caf animals had increased %EWAT (LP-con: 1.11 +/- 0.06 vs. LP-caf: 1.44 +/- 0.08, P < 0.05) and adiponectin (microg/ml: LP-con: 5.38 +/- 0.39 vs. LP-caf: 3.75 +/- 0.35, P < 0.05) but did not show cafeteria-induced hyperinsulinemia or relative hyperleptinemia. An increased propensity to store visceral fat in LP animals may prevent the elevated IS in LP offspring.

Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action.

OBJECTIVE: Berberine (BBR) activates AMP-activated protein kinase (AMPK) and improves insulin sensitivity in rodent models of insulin resistance. We investigated the mechanism of activation of AMPK by BBR and explored whether derivatization of BBR could improve its in vivo efficacy. RESEARCH DESIGN AND METHODS: AMPK phosphorylation was examined in L6 myotubes and LKB1(-/-) cells, with or without the Ca(2+)/calmodulin-dependent protein kinase kinase (CAMKK) inhibitor STO-609. Oxygen consumption was measured in L6 myotubes and isolated muscle mitochondria. The effect of a BBR derivative, dihydroberberine (dhBBR), on adiposity and glucose metabolism was examined in rodents fed a high-fat diet. RESULTS; We have made the following novel observations: 1) BBR dose-dependently inhibited respiration in L6 myotubes and muscle mitochondria, through a specific effect on respiratory complex I, similar to that observed with metformin and rosiglitazone; 2) activation of AMPK by BBR did not rely on the activity of either LKB1 or CAMKKbeta, consistent with major regulation at the level of the AMPK phosphatase; and 3) a novel BBR derivative, dhBBR, was identified that displayed improved in vivo efficacy in terms of counteracting increased adiposity, tissue triglyceride accumulation, and insulin resistance in high-fat-fed rodents. This effect is likely due to enhanced oral bioavailability. CONCLUSIONS: Complex I of the respiratory chain represents a major target for compounds that improve whole-body insulin sensitivity through increased AMPK activity. The identification of a novel derivative of BBR with improved in vivo efficacy highlights the potential importance of BBR as a novel therapy for the treatment of type 2 diabetes.

Maternal undernutrition reduces aortic wall thickness and elastin content in offspring rats without altering endothelial function.

Epidemiological studies suggest a link between fetal/early infant nutrition and adult coronary artery disease. In the present study, we examined the effects of altering nutrition during gestation, lactation and juvenile life on aortic structure and function in rats. Wistar rat dams were fed either a control or low-protein diet throughout pregnancy, or a low-protein diet for the final 7 days of gestation only. At 21 days post-partum, male pups were weaned on to a control, low-protein or high-fat diet. At 12 weeks, the offspring rats were killed. In 46 rats, aortic sections were mounted and stained to assess media thickness and elastin content. In a further 38 rats, aortic rings were suspended in an organ bath and vascular reactivity was tested with dose-response curves to the endothelium-dependent dilator acetylcholine and the endothelium-independent dilator sodium nitroprusside. Rats exposed to maternal protein restriction while in utero had a significantly decreased aortic wall thickness compared with control rats (P=0.005). Total elastin content of the aorta was also decreased by both maternal low-protein (P=0.02) and early postnatal low-protein (P=0.01) diets. Neither maternal nor postnatal low-protein or high-fat diets, however, resulted in any significant changes in arterial dilator function. In conclusion, fetal undernutrition in rats, induced via a maternal low-protein diet, causes a decrease in aortic wall thickness and elastin content without altering aortic dilator function. These changes in vascular structure may amplify aging-related changes to the vasculature and contribute to the pathophysiology of the putative link between impaired fetal growth and adult cardiovascular disease.

Association of the TNF-alpha -308 G/A promoter polymorphism with insulin resistance in obesity.

OBJECTIVE: Obesity is a major risk factor for the development of type 2 diabetes. Tumor necrosis factor (TNF)-alpha is a candidate gene for the development of both obesity and insulin resistance. We investigated whether a common polymorphism in the promoter region (-308 G/A) of the TNF-alpha gene was associated with increased risk for the development of insulin resistance and cardiovascular disease in an obese Australian population. RESEARCH METHODS AND PROCEDURES: Obese, non-diabetic subjects (146 women and 34 men) were genotyped with polymerase chain reaction-restriction fragment length polymorphism techniques, and anthropometric and biochemical measurements were analyzed. A homeostasis model assessment (HOMA) score was used to gauge the level of insulin resistance. RESULTS: The frequencies of the G allele and the A allele were 0.759 and 0.241, respectively. Subjects homozygous for the A allele had higher fasting insulin levels (226 vs. 131 pM; p < 0.001), higher HOMA scores (10.2 vs. 5.3; p < 0.001), higher systolic blood pressure (143 vs. 129 mm Hg; p = 0.02), and lower high-density lipoprotein (HDL) cholesterol (1.13 vs. 1.25 mM; p = 0.04) than did subjects homozygous for the G allele. Whereas an association between insulin resistance and body mass index or waist circumference was seen in all subjects, a highly significant negative correlation of HDL cholesterol to HOMA scores (r = -0.710; p < 0.001) occurred in subjects with the A allele only. DISCUSSION: The -308 G/A TNF-alpha gene variant conveys an increased risk for the development of insulin resistance in obese subjects. The presence of low HDL cholesterol levels further increases the risks associated with insulin resistance in carriers of the A allele.

Maternal protein restriction increases hepatic glycogen storage in young rats.

This study aimed to determine whether maternal protein restriction alters hepatic glycogen metabolism. Mated female rats were fed diets containing 20% protein throughout pregnancy and lactation (CONT), 8% protein throughout pregnancy and lactation (LP), or 8% protein during the last week of pregnancy only and lactation (LLP). Weights and lengths were reduced in the LLP and LP offspring compared with the CONT offspring. The LLP and LP offspring demonstrated reduced insulin concentrations at both 10 and 26 d and also failed to show the increase in insulin seen with time in the CONT offspring. Serum glucose and leptin levels increased with time but were not different among the groups; however, in relation to adiposity leptin levels were greater in the LLP and LP offspring at 26 d. The LLP and LP offspring had increased hepatic glycogen at day 10 (CONT, 75.1 +/- 9.8; LLP, 103.4 +/- 11.0; LP, 116.0 +/- 18.4 glucose residues/g tissue) and d 26 (CONT, 183.1 +/- 38.9; LLP, 395.3 +/- 16.8; LP, 396.6 +/- 15.1 glucose residues/g tissue). Glycogen synthase expression was increased in the LLP and LP offspring at 10 d but not 26 d; glucose transporter 2 and glycogen phosphorylase expressions were not different at either time. At 26 d glycogen synthase activity was not different; however, glycogen phosphorylase a activity was reduced. The enhanced capacity to store glycogen despite reductions in insulin secretion suggests increased insulin sensitivity possibly acting with an alternative non-insulin-dependent glycogen storage mechanism.

Site-specific changes in the expression of fat-partitioning genes in weanling rats exposed to a low-protein diet in utero.

OBJECTIVE: Intrauterine growth restriction is associated with increased prevalence of the metabolic syndrome in adult life, including increased adiposity. The aim of this study was to investigate if maternal protein energy malnutrition is associated with changes in expression of genes involved in fat partitioning in weanling rats. RESEARCH METHODS AND PROCEDURES: Time-mated mothers were placed on one of two isocaloric diets, low protein [(LP), 8% protein] or control (20% protein). All mothers remained on the diet throughout pregnancy and lactation. A third group received control for 2 weeks and was switched to LP for the last week of pregnancy and lactation [late low protein (LLP) group]. Offspring were analyzed at weaning for serum glucose, nonesterified fatty acids, triglyceride, and insulin. Expression of the genes acetyl-coenzyme A carboxylase, fatty acid synthase, and carnitine palmitoyl transferase 1 were measured in liver, quadriceps muscle, and subcutaneous white adipose tissue using semiquantitative reverse transcription-polymerase chain reaction. RESULTS: LLP and LP offspring were shorter, weighed less, had reduced serum insulin and nonesterified fatty acids, and had increased serum glucose, serum triglycerides, and hepatic triglycerides. Hepatic gene expression of acetyl-coenzyme A carboxylase and fatty acid synthase was increased 2-fold in LLP and LP offspring (p < 0.001). These changes were not seen in muscle or subcutaneous white adipose tissue. CPT-1 gene expression was unaltered in all tissues examined. DISCUSSION: Maternal protein energy malnutrition programs gene expression of lipogenic enzymes in the liver of weanling offspring in a manner favoring fat synthesis that may predispose these offspring to fat accumulation and insulin resistance later in life.