Identification of Behavioral and Metabolic Factors Predicting Adiposity Sensitivity to Both High Fat and High Carbohydrate Diets in Rats

Individuals exhibit a great variation in their body weight (BW) gain response to a high fat diet. Identification of predictive factors would enable better directed intervention toward susceptible individuals to treat obesity, and uncover potential mechanisms for treatment targeting. We set out to identify predictive behavioral and metabolic factors in an outbred rat model. 12 rats were analyzed in metabolic cages for a period of 5 days during both high carbohydrate diet (HCD), and transition to a high fat diet (HFD). After a recovery period, rats were given a HFD for 6 days to identify those resistant or sensitive to it according to BW gain. Rats were dissected at the end of the study to analyze body composition. This showed that small differences in final BW hid large variations in adiposity, allowing separation of rats into a second classification (final adiposity). Since these rats had been fed a HCD during most of their life, under which most of the adiposity presumably evolved, we considered this carbohydrate-sensitivity or -resistance. Meal size and meal number were found to be good predictors of sensitivity to a HFD, intensity of motor activity and ingestion speed good predictors of sensitivity to a HCD. Rats that were sensitive to the HCD could be resistant to the HFD and vice versa. This points to four types of individuals (carbohydrate/fat resistant/sensitive) though our sample size inhibited deeper investigation of this. This contributes to the idea that to be “obesity prone” does not necessarily need a HFD, it can also happen under a HCD, and be a hidden adiposity change with stable BW

Low protein/low methionine/high carbohydrate diets induce hyperphagia, increase energy expenditure and FGF21, but modestly affect adiposity infemale BalbC mice.

International audienceTitle: Low protein/low methionine/high carbohydrate diets induce hyperphagia, increase energy expenditure and FGF21, but modestly affect adiposity in female BalbC mice ABSTRACT PREVIEW Author(s)ObjectivesLow-protein diets are reported to induce hyperphagia in an effort to fulfil protein needsbut at the expense of energy balance with a risk to gain in adiposity. However, differentstudies conducted on low-protein diets in animal and human did not confirm weight andbody fat gain because an increased energy expenditure compensated more or lesscompletely for the increase in energy intake and prevents the gain in adiposity. Thepresent study evaluated in mice the consequence of protein restricted diets combined withprotein quality (milk protein versus soy protein with slight methionine deficiency) onenergy intake, energy expenditure and adiposity and the role of FGF21 in the response tothese protein restricted dietsMethodsThe present study investigated in female BalbC mice the behavioral, metabolic andphenotypic responses to 8 weeks feeding a very low (3%), moderately low (6%) or adequate(20%) dietary protein content and whether methionine scarcity in the dietary protein (Soyprotein vs casein) affected these responses. Food intake, body weigh, adiposity (assessedby DEXA), were measured throughout the study and body composition determined bydissection at the end of the study. Plasma, liver, muscle, adipose tissue and hypothalamussamples were collected for nutrient, hormones and/or gene expression measurements.The different mice groups : P20C 20% casein, P20S 20% soy protein, P6C 6% casein, P6S 6%soy protein, P6S-Cor 6% soy protein corrected for methionine, P3C 3% caseinResultsIn female adult BalbC mice, a decrease in dietary casein from 20% to 6% and 3% increasedenergy intake and slightly increased adiposity, and this response was exacerbated with soyproteins with low methionine content compared to milk protein (figure 1). Lean body masswas reduced in 3% casein fed mice but preserved in all 6% fed mice. The effect on fat masswas however limited because total energy expenditure (TEE) increased to the same extentas energy intake (figure 2). In plasma, when protein was decreased, IGF-1 decreased, FGF21increased and plasma FGF21 was best described by using a combination of dietary proteinlevel, protein to carbohydrate ratio and protein to methionine ratio in the diet (figure 3). Insulinresponse to an oral glucose tolerance test was reduced in soy fed mice and in low-proteinfed mice. Low-protein diets did not affect Ucp1 but increased Fgf21 in brown adiposetissue and increased Fgf21, Fas, and Cd36 in the liver. In the hypothalamus, Npy wasincreased and Pomc was decreased only in 3% casein fed mice.Conclusions In conclusion, reducing dietary protein and protein quality increases energy intake but alsoenergy expenditure resulting in an only slight increase in adiposity. In this process FGF21 isprobably an important signal that responds to a complex combination of proteinrestriction, protein quality and carbohydrate content of the diet

Increasing Protein at the Expense of Carbohydrate in the Diet Down-Regulates Glucose Utilization as Glucose Sparing Effect in Rats

High protein (HP) diet could serve as a good strategy against obesity, provoking the changes in energy metabolic pathways. However, those modifications differ during a dietary adaptation. To better understand the mechanisms involved in effect of high protein diet (HP) on limiting adiposity in rats we studied in parallel the gene expression of enzymes involved in protein and energy metabolism and the profiles of nutrients oxidation. Eighty male Wistar rats were fed a normal protein diet (NP, 14% of protein) for one week, then either maintained on NP diet or assigned to a HP diet (50% of protein) for 1, 3, 6 and 14 days. mRNA levels of genes involved in carbohydrate and lipid metabolism were measured in liver, adipose tissues, kidney and muscles by real time PCR. Energy expenditure (EE) and substrate oxidation were measured by indirect calorimetry. Liver glycogen and plasma glucose and hormones were assayed. In liver, HP feeding 1) decreased mRNA encoding glycolysis enzymes (GK, L-PK) and lipogenesis enzymes(ACC, FAS), 2) increased mRNA encoding gluconeogenesis enzymes (PEPCK), 3) first lowered, then restored mRNA encoding glycogen synthesis enzyme (GS), 4) did not change mRNA encoding β-oxidation enzymes (CPT1, ACOX1, βHAD). Few changes were seen in other organs. In parallel, indirect calorimetry confirmed that following HP feeding, glucose oxidation was reduced and fat oxidation was stable, except during the 1st day of adaptation where lipid oxidation was increased. Finally, this study showed that plasma insulin was lowered and hepatic glucose uptake was decreased. Taken together, these results demonstrate that following HP feeding, CHO utilization was increased above the increase in carbohydrate intake while lipogenesis was decreased thus giving a potential explanation for the fat lowering effect of HP diets

Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009

Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD). Multiple prospective studies have documented an association between insulin resistance and accelerated CVD in patients with type 2 diabetes, as well as in non-diabetic individuals. The molecular causes of insulin resistance, i.e. impaired insulin signalling through the phosphoinositol-3 kinase pathway with intact signalling through the mitogen-activated protein kinase pathway, are responsible for the impairment in insulin-stimulated glucose metabolism and contribute to the accelerated rate of CVD in type 2 diabetes patients. The current epidemic of diabetes is being driven by the obesity epidemic, which represents a state of tissue fat overload. Accumulation of toxic lipid metabolites (fatty acyl CoA, diacylglycerol, ceramide) in muscle, liver, adipocytes, beta cells and arterial tissues contributes to insulin resistance, beta cell dysfunction and accelerated atherosclerosis, respectively, in type 2 diabetes. Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis. Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients

Régulation de l'expression des gènes de la glycolyse et de la lipogénèse au niveau du foie par l'insuline et le glucose (rôle du facteur de transcription SREBP-1c et de l'"AMP activated protein kinase")

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Protein metabolism and related body function: mechanistic approaches and health consequences

International audienceThe development and maintenance of body composition and functions require an adequate protein intake with a continuous supply of amino acids (AA) to tissues. Body pool and AA cellular concentrations are tightly controlled and maintained through AA supply (dietary intake, recycled from proteolysis and de novo synthesis), AA disposal (protein synthesis and other AA-derived molecules) and AA losses (deamination and oxidation). Different molecular regulatory pathways are involved in the control of AA sufficiency including the mechanistic target of rapamycin complex 1, the general control non-derepressible 2/activating transcription factor 4 system or the fibroblast growth factor 21. There is a tight control of protein intake, and human subjects and animals appear capable of detecting and adapting food and protein intake and metabolism in face of foods or diets with different protein contents. A severely protein deficient diet induces lean body mass losses and ingestion of sufficient dietary energy and protein is a prerequisite for body protein synthesis and maintenance of muscle, bone and other lean tissues and functions. Maintaining adequate protein intake with age may help preserve muscle mass and strength but there is an ongoing debate as to the optimal protein intake in older adults. The protein synthesis response to protein intake can also be enhanced by prior completion of resistance exercise but this effect could be somewhat reduced in older compared to young individuals and gain in muscle mass and function due to exercise require regular training over an extended period

AMP-activated protein kinase and hepatic genes involved in glucose metabolism.

International audienceMammalian AMP-activated protein kinase presents strong structural and functional similarities with the yeast sucrose non-fermenting 1 (Snf1) kinase involved in the derepression of glucose-repressed genes. It is now clearly established that AMP-activated protein kinase in the liver decreases glycolytic/lipogenic gene expression as well as genes involved in hepatic glucose production. This is achieved through a decreased transcriptional efficiency of transcription factors such as sterol-regulatory-element-binding protein-1c, carbohydrate-response-element-binding protein, hepatocyte nuclear factor 4 alpha or forkhead-related protein. Clearly, the long-term consequences of AMP-activated protein kinase activation have to be taken into account if activators of this enzyme are to be designed as anti-diabetic drugs

Dietary protein and blood glucose control

International audienceTome´Purpose of review This review presents the different pathways by which protein and amino acid impact glucose control. The review more particularly discusses the contradictory effects reported in the literature on the involvement of amino acid on glucose production and in insulin secretion and sensitivity. Recent findings Some recent findings allow a better understanding of the direct and indirect mechanisms involved in the insulinotropic activity of some amino acids in pancreatic b-cell and in the production of glucose through liver gluconeogenesis that participates to improve the control of glycemia. In contrast, the potential deleterious effects of branched chain amino acid, and particularly leucine, hypothesized in previous publications, have been discussed in some recent publications. Summary These processes are of high clinical relevance since the role of protein and amino acid have been repeatedly discussed to improve insulin secretion in type 2 diabetes patients or in weight management strategy in overweight and obese individuals. In addition, whether blood amino acid could be used as biomarkers for the risk of type 2 diabetes needs to be discussed