Impact of sustained calorie restriction and weight cycling on body composition in high-fat diet-fed male and female C57BL/6J mice.

OBJECTIVE: The objective of this study was to investigate body composition changes with weight cycling (WC) among adult C57BL/6J mice with diet-induced obesity. METHODS: A total of 555 single-housed mice were fed a high-fat diet ad libitum (AL) from 8 to 43 weeks of age. The 200 heaviest mice of each sex were randomized to the following four groups: ever obese (EO, continued AL feeding); obese weight loser (OWL, calorie-restricted); obese weight loser moderate (OWLM, body weight halfway between EO and OWL); and WC (diet restricted to OWL followed by AL refeeding cycles). Body weight and composition data were collected. Linear regression was used to calculate residuals between predicted and observed fat mass. Linear mixed models were used to compare diet groups. RESULTS: Although weight loss and regain resulted in changes in body weight and composition, fat mass, body weight, and relative body fat were not significantly greater for the WC group compared with the EO group. During long-term calorie restriction, males (but not females) in the OWLM group remained relatively fatter than the EO group. CONCLUSIONS: WC did not increase body weight or relative fat mass for middle-aged, high-fat diet-fed adult mice. However, long-term moderate calorie restriction resulted in lower body weight but greater "relative" fat in male mice.

Adiposity, reproductive and metabolic health, and activity levels in zoo Asian elephant (Elephas maximus).

Many captive Asian elephant populations are not self-sustaining, possibly due in part to obesity-related health and reproductive issues. This study investigated relationships between estimated body composition and metabolic function, inflammatory markers, ovarian activity (females only) and physical activity levels in 44 Asian elephants (n=35 females, n=9 males). Deuterium dilution was used to measure total body water from which fat mass (FM) and fat-free mass (FFM) could be derived to estimate body composition. Serum was analyzed for progestagens and estradiol (females only), deuterium, glucose, insulin and amyloid A. Physical activity was assessed by an accelerometer placed on the elephant's front leg for at least 2 days. Relative fat mass (RFM) - the amount of fat relative to body mass - was calculated to take differences in body size between elephants into consideration. Body fat percentage ranged from 2.01% to 24.59%. Male elephants were heavier (P=0.043), with more FFM (P=0.049), but not FM (P>0.999), than females. For all elephants, estimated RFM (r=0.45, P=0.004) was positively correlated with insulin. Distance walked was negatively correlated with age (r=-0.46, P=0.007). When adjusted for FFM and age (P<0.001), non-cycling females had less fat compared with cycling females, such that for every 100 kg increase in FM, the odds of cycling were 3 times higher (P<0.001). More work is needed to determine what an unhealthy amount of fat is for elephants; however, our results suggest higher adiposity may contribute to metabolic perturbations.

Fat mass compared to four body condition scoring systems in the Asian elephant (Elephas maximus).

Captive elephant populations are not self-sustaining due to health concerns possibly related to obesity. Categorizing obesity relies on qualitative analyses like body condition scores (BCS). However, elephant indices have not been validated against measured body composition. The objective was to compare BCS systems to body composition determined by deuterium dilution in 28 zoo-kept Asian elephants. Elephants were weighed and given deuterated water orally (0.05 ml/kg). Blood was collected at ~0, 24, 120, 240, 360, and 480 hr after dosing. Photographs were taken to score the elephant based on four BCS systems (BCSWemmer [0 to 11 scoring], BCSMorfeld [1 to 5 scoring], BCSFernando [0 to 10 scoring], BCSWijeyamohan [1 to 10 scoring]). Based on regression analysis, relative fat ranged from -305 kg to 515 kg, where negative values indicate less and positive values indicate more fat than expected for the elephant's mass in this population. BCSFernando was associated with relative fat (p = .020, R2 = 0.194). Relative fat, adjusted for sex and age in the statistical model, was associated with BCSWemmer (p = .027, R2 = 0.389), BCSFernando (p = .002, R2 = 0.502), and BCSWijeyamohan (p = .011, R2 = 0.426). Inclusion of zoo and familial relatedness resulted in all BCS systems associated with relative fat (p ≤ .015). Only BCSFernando predicted relative fat, unadjusted, suggesting it is the most capable system for practical use. Compared to absolute fat, relative fat may be more biologically relevant as greater fat relative to body mass is more likely to lead to health issues.

The translation of age-related body composition findings from rodents to humans.

The objective of this review is to highlight changes in body composition in rodent models as a result of healthy aging in order to enhance translational research. Aging is associated with alterations in body composition, particularly fat mass and fat-free mass, which may be accompanied by adverse health effects, especially nearing middle age to old age. In humans, it is generally understood that fat mass tends to increase while fat-free mass concurrently declines with aging. However, the effect of aging on body composition in rodent models is less well studied, and how these changes compare and contrast with observations in humans has not yet been fully elucidated. Though, it appears as though the constituent-level alterations occur in humans and rodents at different life phases thereby having a potential effect on the outcomes of basic biomedical research. Though highly strain-dependent, this review suggests that FM changes begin at a much earlier life phase in rodents than in humans. Conversely, FFM appears to increase throughout middle age and into old age in rodents, whereas middle age is associated with the initiation the subsequent decline of FFM in humans. Given the essentiality of rodent models in basic biomedical research, careful consideration of these differences in age-related BC findings is imperative when the research is aimed for human translation.

Mks6 mutations reveal tissue- and cell type-specific roles for the cilia transition zone.

The transition zone (TZ) is a domain at the base of the cilium that is involved in maintaining ciliary compartment-specific sensory and signaling activity by regulating cilia protein composition. Mutations in TZ proteins result in cilia dysfunction, often causing pleiotropic effects observed in a group of human diseases classified as ciliopathies. The purpose of this study is to describe the importance of the TZ component Meckel-Grüber syndrome 6 ( Mks6) in several organ systems and tissues regarding ciliogenesis and cilia maintenance using congenital and conditional mutant mouse models. Similar to MKS, congenital loss of Mks6 is embryonic lethal, displaying cilia loss and altered cytoskeletal microtubule modifications but only in specific cell types. Conditional Mks6 mutants have a variable cystic kidney phenotype along with severe retinal degeneration with mislocalization of phototransduction cascade proteins. However, other phenotypes, such as anosmia and obesity, which are typically associated with cilia and TZ dysfunction, were not evident. These data indicate that despite Mks6 being a core TZ component, it has tissue- or cell type-specific functions important for cilia formation and cilia sensory and signaling activities. Lewis, W. R., Bales, K. L., Revell, D. Z., Croyle, M. J., Engle, S. E., Song, C. J., Malarkey, E. B., Uytingco, C. R., Shan, D., Antonellis, P. J., Nagy, T. R., Kesterson, R. A., Mrug, M. M., Martens, J. R., Berbari, N. F., Gross, A. K., Yoder, B. K. Mks6 mutations reveal tissue- and cell type-specific roles for the cilia transition zone.

Weight Cycling Increases Longevity Compared with Sustained Obesity in Mice.

OBJECTIVE: Despite the known health benefits of weight loss among persons with obesity, observational studies have reported that cycles of weight loss and regain, or weight cycling, are associated with increased mortality. To study whether weight loss must be sustained to achieve health and longevity benefits, we performed a randomized controlled feeding study of weight cycling in mice. METHODS: In early adult life, obese mice were randomized to ad libitum feeding to sustain obesity, calorie restriction to achieve a "normal" or intermediate body weight, or weight cycling (repeated episodes of calorie restriction and ad libitum refeeding). Body weight, body composition, and food intake were followed longitudinally until death. A subsample of mice was collected from each group for determination of adipose cell size, serum analytes, and gene expression. RESULTS: Weight loss significantly reduced adipose mass and adipocyte size in both sexes, whereas weight cycling animals regained body fat and cell size during refeeding. Sustained weight loss resulted in a dose-dependent decrease in mortality compared with ad libitum feeding. CONCLUSIONS: Weight cycling significantly increased life-span relative to remaining with obesity and had a similar benefit to sustained modest weight loss.

No Significant Effect of Maternal Perception of the Food Environment on Reproductive Success or Pup Outcomes in C57BL/6J Mice.

OBJECTIVE: Prior work concerning maternal perception of the food environment suggests that perceived disparities in food resources resulted in reduced pup mass and dam reproductive success. This study attempted to replicate this result with increased sample size and additional measures. METHODS: Female C57BL/6J mice (n = 160; 3 weeks old) were randomly assigned to either subject or peer and were pair housed in partitioned cages with olfactory and visual contact. After a 6-week maturation period on an energy-rich cafeteria diet, cages were randomly assigned to Control (subject and peer fed pelleted diet) or Treatment (subject fed pellets, peer fed cafeteria diet), and subjects were bred. After weaning, one pup from each sex per litter was reared to 5 months. RESULTS: Treatment did not affect the number of births, pup size at birth, or the proportion of pups surviving to weaning (P > 0.09). Treatment did not affect dam body or fat mass at parturition (P > 0.22), but these measures were higher in some Treatment dams at weaning (P < 0.05). Smaller female pups were weaned from Treatment dams pregnant on the first breeding attempt (P = 0.01), but no other pup effects were observed (P > 0.07). CONCLUSIONS: Exposure to food-environment disparity in this study did not replicate previous findings or affect pup growth after weaning.

Adiposity and Reproductive Cycling Status in Zoo African Elephants.

OBJECTIVE: The majority of zoo African elephants exhibit abnormal reproductive cycles, but it is unclear why. Acyclicity has been positively associated with body condition scores. The objective of this study was to measure body composition and examine the relationship between adiposity and cyclicity status, mediated by glucose, insulin, leptin, and inflammation. METHODS: Body composition was assessed by deuterium dilution in 22 African elephants. Each elephant was weighed and given deuterated water orally (0.05 mL/kg), and blood was collected from the ear prior to and five times after deuterium administration. Glucose, insulin, leptin, and proinflammatory biomarker concentrations in serum were determined. RESULTS: Body fat percentage ranged from 5.24% to 15.97%. Fat adjusted for fat free mass (FFM) and age was not significantly associated with cyclicity status (P = 0.332). Age was the strongest predictor of cyclicity status (P = 0.040). Fat was correlated with weight (ρ = 0.455, P = 0.044) and when adjusted for FFM with circulating glucose (ρ = 0.520, P = 0.022) and showed a trend for association with leptin (unadjusted: ρ = 0.384, P = 0.095; adjusted for FFM: ρ = 0.403, P = 0.087). CONCLUSIONS: Deuterium dilution appears to be an available technique to measure body composition in African elephants. In this sample, fat was not associated with cyclicity status, and age may be more important to cyclicity status.

High-intensity interval training and calorie restriction promote remodeling of glucose and lipid metabolism in diet-induced obesity.

Calorie restriction (CR) decreases adiposity, but the magnitude and defense of weight loss is less than predicted due to reductions in total daily energy expenditure (TEE). The purpose of the current investigation was to determine whether high-intensity interval training (HIIT) would increase markers of sympathetic activation in white adipose tissue (WAT) and rescue CR-mediated reductions in EE to a greater extent than moderate-intensity aerobic exercise training (MIT). Thirty-two 5-wk-old male C57BL/6J mice were placed on ad libitum HFD for 11 wk, followed by randomization to one of four groups (n = 8/group) for an additional 15 wk: 1) CON (remain on HFD), 2) CR (25% lower energy intake), 3) CR + HIIT (25% energy deficit created by 12.5% CR and 12.5% EE through HIIT), and 4) CR + MIT (25% energy deficit created by 12.5% CR and 12.5% EE through MIT). Markers of adipose thermogenesis (Ucp1, Prdm16, Dio2, and Fgf21) were unchanged in either exercise group in inguinal or epididymal WAT, whereas CR + HIIT decreased Ucp1 expression in retroperitoneal WAT and brown adipose tissue. HIIT rescued CR-mediated reductions in lean body mass (LBM) and resting energy expenditure (REE), and both were associated with improvements in glucose/insulin tolerance. Improvements in glucose metabolism in the CR + HIIT group appear to be linked to a molecular signature that enhances glucose and lipid storage in skeletal muscle. Exercise performed at either moderate or high intensity does not increase markers of adipose thermogenesis when performed in the presence of CR but remodels skeletal muscle metabolic and thermogenic capacity.

Validation of Dual-energy X-Ray Absorptiometry to Predict Body Composition of Channel Catfish, Ictalurus punctatus.

Dual-energy X-ray absorptiometry (DXA) provides a noninvasive way to determine lean tissue mass (LTM), fat mass (FM), bone mineral content (BMC), and bone mineral density (BMD) in humans and small mammals. Live channel catfish (n=74, 78g - 1200 g) were anesthetized and scanned in both a lateral position and a dorsa-ventral position. Six individual fish (300g - 600g) were scanned five times each to determine precision by the coefficient of variation. Precision was good for LTM (0.75-1.06%) and for BMC and BMD (2-2.6%). Precision for FM was not good (27-34%), which was due to the very low FM (0-1g) recorded by the DXA. However, using the predicted values, FM precision improved to 5-5.5%. DXA values for LTM, FM, and BMC were significantly different from chemical analysis (P< 0.001). DXA overestimated LTM and underestimated FM and BMC. However, all three compartments were strongly correlated with carcass values (P <0.0001). Using the prediction equations and the jackknife procedure, predicted values of LTM, FM, and BMC were not significantly different from the carcass values (P >0.05). DXA may also be a valuable tool for evaluating body condition longitudinally in commercial or in threatened or endangered fish species, where non-invasive procedures would be invaluable.

Validation of Body Condition Indices and Quantitative Magnetic Resonance in Estimating Body Composition in a Small Lizard.

Measurements of body condition are typically used to assess an individual's quality, health, or energetic state. Most indices of body condition are based on linear relationships between body length and mass. Although these indices are simple to obtain, nonlethal, and useful indications of energetic state, their accuracy at predicting constituents of body condition (e.g., fat and lean mass) are often unknown. The objectives of this research were to (1) validate the accuracy of another simple and noninvasive method, quantitative magnetic resonance (QMR), at estimating body composition in a small-bodied lizard, Anolis sagrei, and (2) evaluate the accuracy of two indices of body condition (based on length-mass relationships) at predicting body fat, lean, and water mass. Comparisons of results from QMR scans to those from chemical carcass analysis reveal that QMR measures body fat, lean, and water mass with excellent accuracy in male and female lizards. With minor calibration from regression equations, QMR will be a reliable method of estimating body composition of A. sagrei. Body condition indices were positively related to absolute estimates of each constituent of body composition, but these relationships showed considerable variation around regression lines. In addition, condition indices did not predict fat, lean, or water mass when adjusted for body mass. Thus, our results emphasize the need for caution when interpreting body condition based upon linear measurements of animals. Overall, QMR provides an alternative noninvasive method for accurately measuring fat, lean, and water mass in these small-bodied animals.

Observational research rigour alone does not justify causal inference.

BACKGROUND: Differing opinions exist on whether associations obtained in observational studies can be reliable indicators of a causal effect if the observational study is sufficiently well controlled and executed. MATERIALS AND METHODS: To test this, we conducted two animal observational studies that were rigorously controlled and executed beyond what is achieved in studies of humans. In study 1, we randomized 332 genetically identical C57BL/6J mice into three diet groups with differing food energy allotments and recorded individual self-selected daily energy intake and lifespan. In study 2, 60 male mice (CD1) were paired and divided into two groups for a 2-week feeding regimen. We evaluated the association between weight gain and food consumption. Within each pair, one animal was randomly assigned to an S group in which the animals had free access to food. The second paired animal (R group) was provided exactly the same diet that their S partner ate the day before. RESULTS: In study 1, across all three groups, we found a significant negative effect of energy intake on lifespan. However, we found a positive association between food intake and lifespan among the ad libitum feeding group: 29·99 (95% CI: 8·2-51·7) days per daily kcal. In study 2, we found a significant (P = 0·003) group (randomized vs. self-selected)-by-food consumption interaction effect on weight gain. CONCLUSION: At least in nutrition research, associations derived from observational studies may not be reliable indicators of causal effects, even with the most rigorous study designs achievable.

Maternal Western diet increases adiposity even in male offspring of obesity-resistant rat dams: early endocrine risk markers.

Maternal overnutrition or associated complications putatively mediate the obesogenic effects of perinatal high-fat diet on developing offspring. Here, we tested the hypothesis that a Western diet developmental environment increases adiposity not only in male offspring from obesity-prone (DIO) mothers, but also in those from obesity-resistant (DR) dams, implicating a deleterious role for the Western diet per se. Selectively bred DIO and DR female rats were fed chow (17% kcal fat) or Western diet (32%) for 54 days before mating and, thereafter, through weaning. As intended, despite chow-like caloric intake, Western diet increased prepregnancy weight gain and circulating leptin levels in DIO, but not DR, dams. Yet, in both genotypes, maternal Western diet increased the weight and adiposity of preweanlings, as early as in DR offspring, and increased plasma leptin, insulin, and adiponectin of weanlings. Although body weight normalized with chow feeding during adolescence, young adult Western diet offspring subsequently showed decreased energy expenditure and, in DR offspring, decreased lipid utilization as a fuel substrate. By mid-adulthood, maternal Western diet DR offspring ate more chow, weighed more, and were fatter than controls. Thus, maternal Western diet covertly programmed increased adiposity in childhood and adulthood, disrupted relations of energy regulatory hormones with body fat, and decreased energy expenditure in offspring of lean, genetically obesity-resistant mothers. Maternal Western diet exposure alone, without maternal obesity or overnutrition, can promote offspring weight gain.

Increased trabecular bone and improved biomechanics in an osteocalcin-null rat model created by CRISPR/Cas9 technology.

Osteocalcin, also known as bone γ-carboxyglutamate protein (Bglap), is expressed by osteoblasts and is commonly used as a clinical marker of bone turnover. A mouse model of osteocalcin deficiency has implicated osteocalcin as a mediator of changes to the skeleton, endocrine system, reproductive organs and central nervous system. However, differences between mouse and human osteocalcin at both the genome and protein levels have challenged the validity of extrapolating findings from the osteocalcin-deficient mouse model to human disease. The rat osteocalcin (Bglap) gene locus shares greater synteny with that of humans. To further examine the role of osteocalcin in disease, we created a rat model with complete loss of osteocalcin using the CRISPR/Cas9 system. Rat osteocalcin was modified by injection of CRISPR/Cas9 mRNA into the pronuclei of fertilized single cell Sprague-Dawley embryos, and animals were bred to homozygosity and compound heterozygosity for the mutant alleles. Dual-energy X-ray absorptiometry (DXA), glucose tolerance testing (GTT), insulin tolerance testing (ITT), microcomputed tomography (µCT), and a three-point break biomechanical assay were performed on the excised femurs at 5 months of age. Complete loss of osteocalcin resulted in bones with significantly increased trabecular thickness, density and volume. Cortical bone volume and density were not increased in null animals. The bones had improved functional quality as evidenced by an increase in failure load during the biomechanical stress assay. Differences in glucose homeostasis were observed between groups, but there were no differences in body weight or composition. This rat model of complete loss of osteocalcin provides a platform for further understanding the role of osteocalcin in disease, and it is a novel model of increased bone formation with potential utility in osteoporosis and osteoarthritis research.

Relationships between Rodent White Adipose Fat Pads and Human White Adipose Fat Depots.

The objective of this review was to compare and contrast the physiological and metabolic profiles of rodent white adipose fat pads with white adipose fat depots in humans. Human fat distribution and its metabolic consequences have received extensive attention, but much of what has been tested in translational research has relied heavily on rodents. Unfortunately, the validity of using rodent fat pads as a model of human adiposity has received less attention. There is a surprisingly lack of studies demonstrating an analogous relationship between rodent and human adiposity on obesity-related comorbidities. Therefore, we aimed to compare known similarities and disparities in terms of white adipose tissue (WAT) development and distribution, sexual dimorphism, weight loss, adipokine secretion, and aging. While the literature supports the notion that many similarities exist between rodents and humans, notable differences emerge related to fat deposition and function of WAT. Thus, further research is warranted to more carefully define the strengths and limitations of rodent WAT as a model for humans, with a particular emphasis on comparable fat depots, such as mesenteric fat.

Aging and energetics' 'Top 40' future research opportunities 2010-2013.

BACKGROUND: As part of a coordinated effort to expand our research activity at the interface of Aging and Energetics a team of investigators at The University of Alabama at Birmingham systematically assayed and catalogued the top research priorities identified in leading publications in that domain, believing the result would be useful to the scientific community at large. OBJECTIVE: To identify research priorities and opportunities in the domain of aging and energetics as advocated in the 40 most cited papers related to aging and energetics in the last 4 years. DESIGN: The investigators conducted a search for papers on aging and energetics in Scopus, ranked the resulting papers by number of times they were cited, and selected the ten most-cited papers in each of the four years that include 2010 to 2013, inclusive. RESULTS:   Ten research categories were identified from the 40 papers.  These included: (1) Calorie restriction (CR) longevity response, (2) role of mTOR (mechanistic target of Rapamycin) and related factors in lifespan extension, (3) nutrient effects beyond energy (especially resveratrol, omega-3 fatty acids, and selected amino acids), 4) autophagy and increased longevity and health, (5) aging-associated predictors of chronic disease, (6) use and effects of mesenchymal stem cells (MSCs), (7) telomeres relative to aging and energetics, (8) accretion and effects of body fat, (9) the aging heart,  and (10) mitochondria, reactive oxygen species, and cellular energetics. CONCLUSION: The field is rich with exciting opportunities to build upon our existing knowledge about the relations among aspects of aging and aspects of energetics and to better understand the mechanisms which connect them.

Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance.

BACKGROUND: Carnitine Palmitoyl Transferase 1 (CPT1) is the rate-limiting enzyme governing long-chain fatty acid entry into mitochondria. CPT1 inhibitors have been developed and exhibited beneficial effects against type II diabetes in short-term preclinical animal studies. However, the long-term effects of treatment remain unclear and potential non-specific effects of these CPT1 inhibitors hamper in-depth understanding of the potential molecular mechanisms involved. METHODS: We investigated the effects of restricting the activity of the muscle isoform CPT1b in mice using heterozygous CPT1b deficient (Cpt1b+/-) and Wild Type (WT) mice fed with a High Fat Diet (HFD) for 22 weeks. Insulin sensitivity was assessed using Glucose Tolerance Test (GTT), insulin tolerance test and hyperinsulinemic euglycemic clamps. We also examined body weight/composition, tissue and systemic metabolism/energetic status, lipid profile, transcript analysis, and changes in insulin signaling pathways. RESULTS: We found that Cpt1b+/- mice were protected from HFD-induced insulin resistance compared to WT littermates. Cpt1b+/- mice exhibited elevated whole body glucose disposal rate and skeletal muscle glucose uptake. Furthermore, Cpt1b+/- skeletal muscle showed diminished ex vivo palmitate oxidative capacity by ~40% and augmented glucose oxidation capacity by ~50% without overt change in whole body energy metabolism. HFD feeding Cpt1b+/- but not WT mice exhibited well-maintained insulin signaling in skeletal muscle, heart, and liver. CONCLUSION: The present study on a genetic model of CPT1b restriction supports the concept that partial CPT1b inhibition is a potential therapeutic strategy.

Variations in body weight, food intake and body composition after long-term high-fat diet feeding in C57BL/6J mice.

OBJECTIVE: To investigate the variations in body weight, food intake, and body composition of both male and female C57BL/6J mice during a diet-induced obesity model with high-fat diet (HFD) feeding. METHODS: Mice were individually housed and fed ad libitum either a low-fat diet (LFD, 10% calories from fat; n = 15 male, n = 15 female) or HFD (45% calories from fat; n = 277 male, n = 278 female) from 8 to 43 weeks of age. Body weight, food intake, and body composition were routinely measured. RESULTS: Body weight was significantly increased with HFD (vs. LFD) in males from week 14 (P = 0.0221) and in females from week 27 (P = 0.0076). Fat mass and fat-free mass of all groups were significantly increased over time (all P < 0.0001), with a large variation observed in fat mass. Baseline fat mass, fat-free mass, and daily energy intake were significant predictors of future body weight for both sexes (P < 0.0001). Baseline fat mass was a significant predictor of future body fat (P < 0.0001). CONCLUSIONS: Both males and females have large variations in fat mass, and this variability increases over time, while that of fat-free mass remains relatively stable. Sex differences exist in HFD responses and multivariate predicting models of body weight.

Dietary acrylamide and human cancer: a systematic review of literature.

Cancer remains the second leading cause of death in the United States, and the number of cases is expected to continue to rise worldwide. Cancer prevention strategies are crucial for reducing the cancer burden. The carcinogenic potential of dietary acrylamide exposure from cooked foods is unknown. Acrylamide is a by-product of the common Maillard reaction where reducing sugars (i.e., fructose and glucose) react with the amino acid, asparagine. Based on the evidence of acrylamide carcinogenicity in animals, the International Agency for Research on Cancer has classified acrylamide as a group 2A carcinogen for humans. Since the discovery of acrylamide in foods in 2002, a number of studies have explored its potential as a human carcinogen. This article outlines a systematic review of dietary acrylamide and human cancer, acrylamide exposure and internal dose, exposure assessment methods in the epidemiologic studies, existing data gaps, and future directions. A majority of the studies reported no statistically significant association between dietary acrylamide intake and various cancers, and few studies reported increased risk for renal, endometrial, and ovarian cancers; however, the exposure assessment has been inadequate leading to potential misclassification or underestimation of exposure. Future studies with improved dietary acrylamide exposure assessment are encouraged.