Cue-potentiated feeding in rodents: Implications for weight regulation in obesogenic environments.

Cue-potentiated feeding (CPF) describes instances where food intake is increased by exposure to conditioned cues associated with food, often in the absence of hunger. CPF effects have been reported in a range of experimental protocols developed by researchers working across diverse fields spanning behavioural neuroscience, social psychology and ecology. Here we review the evolution of research on cue-potentiated feeding in animal models to identify important behavioural parameters and key neural circuits and pharmacological systems underlying the effect. Overall, evidence indicates that social, discrete and contextual stimuli can be used to elicit CPF effects across multiple species, though effects are often subtle and sensitive to procedural variables. While regular exposure to food cues is thought to be a key risk factor for overeating in so-called 'obesogenic' environments, further work is needed to identify whether CPF promotes positive energy balance and weight gain over the longer term. We suggest several methodological and conceptual areas for inquiry to elucidate the contribution of CPF to the regulation of food choice and energy intake.

Time-restricted feeding does not prevent adverse effects of palatable cafeteria diet on adiposity, cognition and gut microbiota in rats.

Time-restricted feeding (TRF) is a popular dietary strategy whereby daily food intake is limited to a <12h window. As little is known about the effects of TRF on cognitive and behavioural measures, the present study examined the effects of time-restricted (8h/day; zeitgeber time [ZT]12-20) or continuous access to a high-fat, high-sugar cafeteria-style diet (Caf; Caf and Caf-TRF groups; n=12 adult male Sprague-Dawley rats) or standard chow (Chow and Chow-TRF groups) on short-term memory, anxiety-like behaviour, adiposity and gut microbiota composition over 13-weeks with daily food intake measures. TRF significantly reduced daily energy intake in Caf- but not chow-fed groups. In Caf-fed groups, TRF reduced the proportion of energy derived from sugar while increasing that derived from protein. Caf diet significantly increased weight gain, adiposity and fasting glucose within 4 weeks; TRF partially reduced these effects. Caf diet increased anxiety-like behaviour in the Elevated Plus Maze in week 3 but not week 12, and impaired hippocampal-dependent place recognition memory in week 11; neither measure was affected by TRF. Global microbiota composition differed markedly between chow and Caf groups, with a small effect of TRF in rats fed chow. In both chow and Caf diet groups, TRF reduced microbiota alpha diversity measures of Shannon diversity and evenness relative to continuous access. Results indicate only limited benefits of TRF access to an obesogenic diet under these conditions, suggesting that more severe time restriction may be required to offset adverse metabolic and cognitive effects when using highly palatable diets.

Striatal Acetylcholine and Dopamine Interactions Produce Situation-appropriate Action Selection.

Individuals often learn how to perform new actions for particular outcomes against a complex background of existing action-outcome associations. As such, this new knowledge can interfere or even compete with existing knowledge, such that individuals must use internal and external cues to determine which action is appropriate to the current situation. The question thus remains as to how this problem is solved at a neural level. Research over the last decade or so has begun to determine how the brain achieves situation-appropriate action selection. Several converging lines of evidence suggest that it is achieved through the complex interactions of acetylcholine and dopamine within the striatum in a manner that relies on glutamatergic inputs from the cortex and thalamus. Here we briefly review this evidence, then relate it to several very recent findings to provide new, speculative insights regarding the precise nature of striatal acetylcholine/dopamine interaction dynamics and their relation to situation- appropriate action selection.

High fat diet allows food-predictive stimuli to energize action performance in the absence of hunger, without distorting insulin signaling on accumbal cholinergic interneurons.

Obesity can disrupt how food-predictive stimuli control action performance and selection. These two forms of control recruit cholinergic interneurons (CIN) located in the nucleus accumbens core (NAcC) and shell (NAcS), respectively. Given that obesity is associated with insulin resistance in this region, we examined whether interfering with CIN insulin signaling disrupts how food-predictive stimuli control actions. To interfere with insulin signaling we used a high-fat diet (HFD) or genetic excision of the insulin receptor (InsR) from cholinergic cells. HFD left intact the capacity of food-predictive stimuli to energize performance of an action earning food when mice were tested hungry. However, it allowed this energizing effect to persist when the mice were tested sated. This persistence was linked to NAcC CIN activity but was not associated with distorted CIN insulin signaling. Accordingly, InsR excision had no effect on how food-predicting stimuli control action performance. Next, we found that neither HFD nor InsR excision altered the capacity of food-predictive stimuli to guide action selection. Yet, this capacity was associated with changes in NAcS CIN activity. These results indicate that insulin signaling on accumbal CINs does not modulate how food-predictive stimuli control action performance and selection. However, they show that HFD allows food-predictive stimuli to energize performance of an action earning food in the absence of hunger.

Diet and obesity effects on cue-driven food-seeking: insights from studies of Pavlovian-instrumental transfer in rodents and humans.

Our modern environment is said to be obesogenic, promoting the consumption of calorically dense foods and reducing energy expenditure. One factor thought to drive excess energy intake is the abundance of cues signaling the availability of highly palatable foods. Indeed, these cues exert powerful influences over food-related decision-making. Although obesity is associated with changes to several cognitive domains, the specific role of cues in producing this shift and on decision-making more generally, remains poorly understood. Here we review the literature examining how obesity and palatable diets affect the ability of Pavlovian cues to influence instrumental food-seeking behaviors by examining rodent and human studies incorporating Pavlovian-instrumental transfer (PIT) protocols. There are two types of PIT: (a) general PIT that tests whether cues can energize actions elicited in the pursuit of food generally, and (b) specific PIT which tests whether cues can elicit an action that earns a specific food outcome when faced with a choice. Both types of PIT have been shown to be vulnerable to alterations as a result of changes to diet and obesity. However, effects appear to be driven less by increases in body fat and more by palatable diet exposure per se. We discuss the limitations and implications of the current findings. The challenges for future research are to uncover the mechanisms underlying these alterations to PIT, which appear unrelated to excess weight itself, and to better model the complex determinants of food choice in humans.

Switching from Sugar- to Artificially-Sweetened Beverages: A 12-Week Trial.

BACKGROUND: Consumption of sugar-sweetened beverages (SSBs) forms the primary source of added sugar intake and can increase the risk of metabolic disease. Evidence from studies in humans and rodents also indicates that consumption of SSBs can impair performance on cognitive tests, but that removing SSB access can ameliorate these effects. METHODS: The present study used an unblinded 3-group parallel design to assess the effects of a 12-week intervention in which young healthy adults (mean age = 22.85, SD = 3.89; mean BMI: 23.2, SD = 3.6) who regularly consumed SSBs were instructed to replace SSB intake with artificially-sweetened beverages (n = 28) or water (n = 25), or (c) to continue SSB intake (n = 27). RESULTS: No significant group differences were observed in short-term verbal memory on the Logical Memory test or the ratio of waist circumference to height (primary outcomes), nor in secondary measures of effect, impulsivity, adiposity, or glucose tolerance. One notable change was a significant reduction in liking for strong sucrose solutions in participants who switched to water. Switching from SSBs to 'diet' drinks or water had no detectable impact on cognitive or metabolic health over the relatively short time frame studied here. This study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615001004550; Universal Trial Number: U1111-1170-4543).

Obesogenic Diet Cycling Produces Graded Effects on Cognition and Microbiota Composition in Rats.

SCOPE: The effects of diet cycling on cognition and fecal microbiota are not well understood. METHOD AND RESULTS: Adult male Sprague-Dawley rats were cycled between a high-fat, high-sugar "cafeteria" diet (Caf) and regular chow. The impairment in place recognition memory produced by 16 days of Caf diet was reduced by switching to chow for 11 but not 4 days. Next, rats received 16 days of Caf diet in 2, 4, 8, or 16-day cycles, each separated by 4-day chow cycles. Place recognition memory declined from baseline in all groups and was impaired in the 16- versus 2-day group. Finally, rats received 24 days of Caf diet continuously or in 3-day cycles separated by 2- or 4-day chow cycles. Any Caf diet access impaired cognition and increased adiposity relative to controls, without altering hippocampal gene expression. Place recognition and adiposity were the strongest predictors of global microbiota composition. Overall, diets with higher Caf > chow ratios produced greater spatial memory impairments and larger shifts in gut microbiota species richness and beta diversity. CONCLUSION: Results suggest that diet-induced cognitive deficits worsen in proportion to unhealthy diet exposure, and that shifting to a healthy chow for at least a week is required for recovery under the conditions tested here.

Serotonin and Dopamine Show Different Response Profiles to Acute Stress in the Nucleus Accumbens and Medial Prefrontal Cortex of Rats with Neuropathic Pain.

The ability to adaptively guide behaviour requires the integration of external information with internal motivational factors. Decision-making capabilities can be impaired by acute stress and is often exacerbated by chronic pain. Chronic neuropathic pain patients often present with cognitive dysfunction, including impaired decision-making. The mechanisms underlying these changes are not well understood but may include altered monoaminergic transmission in the brain. In this study we investigated the relationships between dopamine, serotonin, and their metabolites in key brain regions that regulate motivated behaviour and decision-making. The neurochemical profiles of the medial prefrontal cortex, orbital prefrontal cortex, and nucleus accumbens were analysed using HPLC in rats that received a chronic constriction injury (CCI) of the right sciatic nerve and an acute stress (15-min restraint), prior to an outcome devaluation task. CCI alone significantly decreased dopamine but not serotonin concentrations in the medial prefrontal cortex. By contrast, restraint stress acutely increased dopamine in the medial prefrontal cortex, and the nucleus accumbens; and increased serotonin in the medial prefrontal cortex 2 h later. The sustained dopaminergic and serotonergic responses to acute stress highlight the importance of an animal's ability to mount an effective coping response. In addition, these data suggest that the impact of nerve injury and acute stress on outcome-devaluation occurs independently of dopaminergic and serotonergic transmission in the medial prefrontal cortex, orbital prefrontal cortex and nucleus accumbens of rats.

The Benefits of Switching to a Healthy Diet on Metabolic, Cognitive, and Gut Microbiome Parameters Are Preserved in Adult Rat Offspring of Mothers Fed a High-Fat, High-Sugar Diet.

SCOPE: Maternal obesity increases the risk of health complications in children, highlighting the need for effective interventions. A rat model of maternal obesity to examine whether a diet switch intervention could reverse the adverse effects of an unhealthy postweaning diet is used. METHODS AND RESULTS: Male and female offspring born to dams fed standard chow or a high-fat, high-sugar "cafeteria" (Caf) diet are weaned onto chow or Caf diets until 22 weeks of age, when Caf-fed groups are switched to chow for 5 weeks. Adiposity, gut microbiota composition, and place recognition memory are assessed before and after the switch. Body weight and adiposity fall in switched groups but remain significantly higher than chow-fed controls. Nonetheless, the diet switch improves a deficit in place recognition memory observed in Caf-fed groups, increases gut microbiota species richness, and alters ß diversity. Modeling indicate that adiposity most strongly predicts gut microbiota composition before and after the switch. CONCLUSION: Maternal obesity does not alter the effects of switching diet on metabolic, microbial, or cognitive measures. Thus, a healthy diet intervention lead to major shifts in body weight, adiposity, place recognition memory, and gut microbiota composition, with beneficial effects preserved in offspring born to obese dams.

Food for thought: diet-induced impairments to decision-making and amelioration by N-acetylcysteine in male rats.

RATIONALE: Attempts to lose weight often fail despite knowledge of the health risks associated with obesity and determined efforts. We previously showed that rodents fed an obesogenic diet displayed premature habitual behavioural control and weakened flexible decision-making based on the current value of outcomes produced by their behaviour. Thus, habitual control may contribute to failed attempts to modify eating behaviours. OBJECTIVES: To examine the effects of an obesogenic diet on behavioural control and glutamate transmission in dorsal striatum regions and to assess the ability of N-acetylcysteine (NAC) to reverse deficits. METHODS: Here, we examined diet-induced changes to decision-making and used in vitro electrophysiology to investigate the effects of diet on glutamate transmission within the dorsomedial (DMS) and dorsolateral (DLS) striatum, areas that control goal-directed and habitual behaviours, respectively. We administered NAC in order to normalize glutamate release and tested whether this would restore goal-directed performance following an obesogenic diet. RESULTS: We found that an obesogenic diet reduced sensitivity to outcome devaluation and increased glutamate release in the DMS, but not DLS. Administration of NAC restored goal-directed control and normalized mEPSCs in the DMS. Finally, NAC administered directly to the DMS was sufficient to reinstate sensitivity to outcome devaluation following an obesogenic diet. CONCLUSIONS: These data indicate that obesogenic diets alter neural activity in the basal ganglia circuit responsible for goal-directed learning and control which leads to premature habitual control. While the effects of diet are numerous and widespread, normalization of glutamatergic activity in this circuit is sufficient for restoring goal-directed behaviour.

Association learning: Dopamine and the formation of backward associations.

The activity of dopamine neurons is critical for the ability to learn and update cue-reward associations. New work in rats shows that dopamine transients are also critical for the formation of backward associations in which the reward precedes the neutral stimulus.

The influence of maternal unhealthy diet on maturation of offspring gut microbiota in rat.

BACKGROUND: Despite well-known effects of diet on gut microbiota diversity, relatively little is known about how maternal diet quality shapes the longitudinal maturation of gut microbiota in offspring. To investigate, we fed female rats standard chow (Chow) or a western-style, high-choice cafeteria diet (Caf) prior to and during mating, gestation and lactation. At weaning (3 weeks), male and female offspring were either maintained on their mother's diet (ChowChow, CafCaf groups) or switched to the other diet (ChowCaf, CafChow). Fecal microbial composition was assessed in dams and longitudinally in offspring at 3, 7 and 14 weeks of age. RESULTS: The effect of maternal diet on maturation of offspring gut microbiota was assessed by α- and ß-diversities, Deseq2/LEfSe, and SourceTracker analyses. Weanling gut microbiota composition was characterised by reduced α- and ß-diversity profiles that clustered away from dams and older siblings. After weaning, offspring gut microbiota came to resemble an adult-like gut microbiota, with increased α-diversity and reduced dissimilarity of ß-diversity. Similarly, Deseq2/LEfSe analyses found fewer numbers of altered operational taxonomic units (OTUs) between groups from weaning to adulthood. SourceTracker analyses indicated a greater overall contribution of Caf mothers' microbial community (up to 20%) to that of their offspring than the contribution of Chow mothers (up to 8%). Groups maintained on the maternal diet (ChowChow, CafCaf), versus those switched to the other diet (ChowCaf, CafChow) post-weaning significantly differed from each other at 14 weeks (Permutational Multivariate Analysis of Variance), indicating interactive effects of maternal and post-weaning diet on offspring gut microbiota maturation. Nevertheless, this developmental trajectory was unaffected by sex and appeared consistent between ChowChow, CafCaf, ChowCaf and CafChow groups. CONCLUSIONS: Introducing solid food at weaning triggered the maturation of offspring gut microbiota to an adult-like profile in rats, in line with previous human studies. Postweaning Caf diet exposure had the largest impact on offspring gut microbiota, but this was modulated by maternal diet history. An unhealthy maternal Caf diet did not alter the developmental trajectory of offspring gut microbiota towards an adult-like profile, insofar as it did not prevent the age-associated increase in α-diversity and reduction in ß-diversity dissimilarity.

Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions.

Diabetic peripheral neuropathy (DPN) affects over half of type 2 diabetes mellitus (T2DM) patients, with an urgent need for effective pharmacotherapies. While many rat and mouse models of T2DM exist, the phenotyping of DPN has been challenging with inconsistencies across laboratories. To better characterize DPN in rodents, a consensus guideline was published in 2014 to accelerate the translation of preclinical findings. Here we review DPN phenotyping in rat models of T2DM against the 'Neurodiab' criteria to identify uptake of the guidelines and discuss how DPN phenotypes differ between models and according to diabetes duration and sex. A search of PubMed, Scopus and Web of Science databases identified 125 studies, categorised as either diet and/or chemically induced models or transgenic/spontaneous models of T2DM. The use of diet and chemically induced T2DM models has exceeded that of transgenic models in recent years, and the introduction of the Neurodiab guidelines has not appreciably increased the number of studies assessing all key DPN endpoints. Combined high-fat diet and low dose streptozotocin rat models are the most frequently used and well characterised. Overall, we recommend adherence to Neurodiab guidelines for creating better animal models of DPN to accelerate translation and drug development.

Male Rat Offspring Are More Impacted by Maternal Obesity Induced by Cafeteria Diet than Females-Additive Effect of Postweaning Diet.

Maternal obesity increases the risk of health complications in offspring, but whether these effects are exacerbated by offspring exposure to unhealthy diets warrants further investigation. Female Sprague-Dawley rats were fed either standard chow (n = 15) or 'cafeteria' (Caf, n = 21) diets across pre-pregnancy, gestation, and lactation. Male and female offspring were weaned onto chow or Caf diet (2-3/sex/litter), forming four groups; behavioural and metabolic parameters were assessed. At weaning, offspring from Caf dams were smaller and lighter, but had more retroperitoneal (RP) fat, with a larger effect in males. Maternal Caf diet significantly increased relative expression of ACACA and Fasn in male and female weanling liver, but not CPT-1, SREBP and PGC1; PPARα was increased in males from Caf dams. Maternal obesity enhanced the impact of postweaning Caf exposure on adult body weight, RP fat, liver mass, and plasma leptin in males but not females. Offspring from Caf dams appeared to exhibit reduced anxiety-like behaviour on the elevated plus maze. Hepatic CPT-1 expression was reduced only in adult males from Caf fed dams. Post weaning Caf diet consumption did not alter liver gene expression in the adult offspring. Maternal obesity exacerbated the obesogenic phenotype produced by postweaning Caf diet in male, but not female offspring. Thus, the impact of maternal obesity on adiposity and liver gene expression appeared more marked in males. Our data underline the sex-specific detrimental effects of maternal obesity on offspring.

Adolescent exposure to a solid high-fat, high-sugar 'cafeteria' diet leads to more pronounced changes in metabolic measures and gut microbiome composition than liquid sugar in female rats.

Adolescence is a dynamic developmental period where unhealthy solid foods and sugar-sweetened beverages are routinely consumed. Regular consumption of solid 'junk' foods rich in fat and refined carbohydrate and sugar-sweetened beverages are independently associated with an increased risk of metabolic disease and altered gut microbiome composition. Here we used a validated rat model to determine the effects of a solid 'cafeteria' diet high in fat and sugar (Caf) and 10% liquid sucrose solution (Suc) on food intake, metabolic measures and gut microbiome composition. Sixty adolescent female Sprague-Dawley rats were fed standard chow with or without continuous access to Caf diet and/or Suc for 13 weeks (n = 15). Exposure to cafeteria diet and liquid sucrose each increased body weight gain and adiposity, with no synergistic effects. Gut microbiome alpha and beta diversity parameters were more strongly affected by exposure to Caf diet than access to liquid Suc. Nonetheless, providing liquid sucrose to rats fed chow altered gut microbiome beta diversity and significantly enriched the abundance of five taxa from order Clostridiales. By contrast, in the two groups fed Caf, Suc did not alter beta diversity, with few differentially abundant taxa between Caf and Caf + Suc groups. In sum, liquid sucrose and solid cafeteria diet exerted largely independent effects on metabolic and gut microbiome measures. Interventions targeting either solid junk foods or sugary beverages are likely to reduce diet-related disease burden.

Chronic exposure to cafeteria-style diet in rats alters sweet taste preference and reduces motivation for, but not 'liking' of sucrose.

Obesity is associated with changes to taste perception and brain reward circuitry. It is important to understand how these effects alter the preference for palatable foods and drinks, given that these are widely consumed, and leading risk factors for obesity. This study examined the effects of diet-induced obesity on sweet taste preference by analysing the microstructure of licking for sugar solutions and assessing pERK expression in the nucleus accumbens shell and insula. Adult male Sprague-Dawley rats were fed standard chow (Control; n = 16) or a varied, palatable cafeteria diet (Caf; n = 16) for 12 weeks. Two-choice preference tests between 2%, 8% and 32% sucrose solutions were conducted at baseline and in weeks 11-12 of the diet. Rats in the Caf group trebled energy intake and doubled weight gain relative to controls. In tests held under water restriction after 11 weeks of diet, the Control group reliably preferred higher sucrose concentrations (i.e., 32% > 8% > 2%). Relative to controls, the Caf group showed a stronger preference for 32% vs. 2% sucrose, lower preference for 32% vs. 8% sucrose, and were indifferent to 8% vs. 2% sucrose. Testing without water restriction increased preference for higher sucrose concentrations in both groups. Chronic Caf diet increased the latency to lick, decreased total licks and reduced alternations between spouts, but did not alter lick cluster size, a measure of hedonic appraisal, on any test. Following a final exposure to a novel sucrose concentration, neuronal activity (pERK) in the insula and nucleus accumbens shell was significantly reduced in the Caf group. Results indicate that differences in 'liking' do not underlie obesity-induced changes to sweet taste preference.

Unravelling the impacts of western-style diets on brain, gut microbiota and cognition.

The steady rise in the prevalence of obesity has been fostered by modern environments that reduce energy expenditure and encourage consumption of 'western'-style diets high in fat and sugar. Obesity has been consistently associated with impairments in executive function and episodic memory, while emerging evidence indicates that high-fat, high-sugar diets can impair aspects of cognition within days, even when provided intermittently. Here we review the detrimental effects of diet and obesity on cognition and the role of inflammatory and circulating factors, compromised blood-brain barrier integrity and gut microbiome changes. We next evaluate evidence for changing risk profiles across life stages (adolescence and ageing) and other populations at risk (e.g. through maternal obesity). Finally, interventions to ameliorate diet-induced cognitive deficits are discussed, including dietary shifts, exercise, and the emerging field of microbiome-targeted therapies. With evidence that poor diet and obesity impair cognition via multiple mechanisms across the human lifespan, the challenge for future research is to identify effective interventions, in addition to diet and exercise, to prevent and ameliorate adverse effects.

Mechanisms Underlying the Cognitive and Behavioural Effects of Maternal Obesity.

The widespread consumption of 'western'-style diets along with sedentary lifestyles has led to a global epidemic of obesity. Epidemiological, clinical and preclinical evidence suggests that maternal obesity, overnutrition and unhealthy dietary patterns programs have lasting adverse effects on the physical and mental health of offspring. We review currently available preclinical and clinical evidence and summarise possible underlying neurobiological mechanisms by which maternal overnutrition may perturb offspring cognitive function, affective state and psychosocial behaviour, with a focus on (1) neuroinflammation; (2) disrupted neuronal circuities and connectivity; and (3) dysregulated brain hormones. We briefly summarise research implicating the gut microbiota in maternal obesity-induced changes to offspring behaviour. In animal models, maternal obesogenic diet consumption disrupts CNS homeostasis in offspring, which is critical for healthy neurodevelopment, by altering hypothalamic and hippocampal development and recruitment of glial cells, which subsequently dysregulates dopaminergic and serotonergic systems. The adverse effects of maternal obesogenic diets are also conferred through changes to hormones including leptin, insulin and oxytocin which interact with these brain regions and neuronal circuits. Furthermore, accumulating evidence suggests that the gut microbiome may directly and indirectly contribute to these maternal diet effects in both human and animal studies. As the specific pathways shaping abnormal behaviour in offspring in the context of maternal obesogenic diet exposure remain unknown, further investigations are needed to address this knowledge gap. Use of animal models permits investigation of changes in neuroinflammation, neurotransmitter activity and hormones across global brain network and sex differences, which could be directly and indirectly modulated by the gut microbiome.

Comparable metabolic effects of isocaloric sucrose and glucose solutions in rats.

Much of the global increase in sugar intake is attributable to rising consumption of sugar-sweetened beverages (SSBs). Because people compensate poorly for liquid calories, SSB consumption increases total energy intake, raising the risk of harmful metabolic effects in addition to possible effects of sugars per se. Glucose and fructose, the constituent sugars in sucrose, can exert distinct effects on metabolism and also differ in their satiating properties, suggesting that compensation for the calories in these sugars may also vary. In light of claims that the fructose within sucrose is particularly harmful, the present study compared the effects of giving rats access to either a sucrose or an isoenergetic glucose solution. Adult male rats were fed standard chow and water supplemented with 95 ml of 10% glucose (Glucose group; n = 10), 9% sucrose solution (Sucrose group; n = 10) or water only (Control group; n = 10) daily for 7 weeks. Sugar-fed groups had higher total energy intakes than the Control group, but the extent of this incomplete compensation did not vary between Sucrose and Glucose groups. In a short-term compensation test, sugar groups were less sensitive to the effects of a sweet pre-meal, with no differences between the Glucose and Sucrose groups. Relative to water, both sugars reduced insulin sensitivity after 4 weeks on the diets and elevated fat mass at 7 weeks. Results suggest that sucrose and glucose induce comparable metabolic impairments and alter the homeostatic regulation of food intake even under conditions where daily access is capped.

Evidence of Altered Peripheral Nerve Function in a Rodent Model of Diet-Induced Prediabetes.

Peripheral neuropathy (PN) is a debilitating complication of diabetes that affects >50% of patients. Recent evidence suggests that obesity and metabolic disease, which often precede diabetes diagnosis, may influence PN onset and severity. We examined this in a translationally relevant model of prediabetes induced by a cafeteria (CAF) diet in Sprague-Dawley rats (n = 15 CAF versus n = 15 control). Neuropathy phenotyping included nerve conduction, tactile sensitivity, intraepidermal nerve fiber density (IENFD) and nerve excitability testing, an in vivo measure of ion channel function and membrane potential. Metabolic phenotyping included body composition, blood glucose and lipids, plasma hormones and inflammatory cytokines. After 13 weeks diet, CAF-fed rats demonstrated prediabetes with significantly elevated fasting blood glucose, insulin and impaired glucose tolerance as well as obesity and dyslipidemia. Nerve conduction, tactile sensitivity and IENFD did not differ; however, superexcitability was significantly increased in CAF-fed rats. Mathematical modeling demonstrated this was consistent with a reduction in sodium-potassium pump current. Moreover, superexcitability correlated positively with insulin resistance and adiposity, and negatively with fasting high-density lipoprotein cholesterol. In conclusion, prediabetic rats over-consuming processed, palatable foods demonstrated altered nerve function that preceded overt PN. This work provides a relevant model for pathophysiological investigation of diabetic complications.