Sex differences in response to short-term high fat diet in mice.

BACKGROUND: Consumption of high-fat diet (HF) leads to hyperphagia and increased body weight in male rodents. Female rodents are relatively resistant to hyperphagia and weight gain in response to HF, in part via effects of estrogen that suppresses food intake and increases energy expenditure. However, sex differences in energy expenditure and activity levels with HF challenge have not been systemically described. We hypothesized that, in response to short-term HF feeding, female mice will have a higher energy expenditure and be more resistant to HF-induced hyperphagia than male mice. METHODS: Six-week-old male and female C57BL/6 J mice were fed either low fat (LF, 10% fat) or moderate HF (45% fat) for 5 weeks, and energy expenditure, activity and meal pattern measured using comprehensive laboratory animal monitoring system (CLAMS). RESULTS: After 5 weeks, HF-fed male mice had a significant increase in body weight and fat mass, compared with LF-fed male mice. HF-fed female had a significant increase in body weight compared with LF-fed female mice, but there was no significant difference in fat mass. HF-fed male mice had lower energy expenditure compared to HF-fed female mice, likely due in part to reduced physical activity in the light phase. HF-fed male mice also had increased energy intake in the dark phase compared to LF-fed male mice and a reduced response to exogenous cholecystokinin-induced inhibition of food intake. In contrast, there was no difference in energy intake between LF-fed and HF-fed female mice. CONCLUSIONS: The data show that female mice are generally protected from short-term HF-induced alterations in energy balance, possibly by maintaining higher energy expenditure and an absence of hyperphagia. However, HF-feeding in male mice induced weight and fat mass gain and hyperphagia. These findings suggest that there is a sex difference in the response to short-term HF-feeding in terms of both energy expenditure and control of food intake.

Deletion of leptin receptors in vagal afferent neurons disrupts estrogen signaling, body weight, food intake and hormonal controls of feeding in female mice.

Deletion of the leptin receptor from vagal afferent neurons (VAN) using a conditional deletion (Nav1.8/LepRfl/fl) results in an obese phenotype with increased food intake and lack of exogenous cholecystokinin (CCK)-induced satiation in male mice. Female mice are partially protected from weight gain and increased food intake in response to ingestion of high-fat (HF) diets. However, whether the lack of leptin signaling in VAN leads to an obese phenotype or disruption of hypothalamic-pituitary-gonadal axis function in female mice is unclear. Here, we tested the hypothesis that leptin signaling in VAN is essential to maintain estrogen signaling and control of food intake, energy expenditure, and adiposity in female mice. Female Nav1.8/LepRfl/fl mice gained more weight, had increased gonadal fat mass, increased meal number in the dark phase, and increased total food intake compared with wild-type controls. Resting energy expenditure was unaffected. The decrease in food intake produced by intraperitoneal injection of CCK (3 µg/kg body wt) was attenuated in female Nav1.8/LepRfl/fl mice compared with wild-type controls. Intraperitoneal injection of ghrelin (100 µg/kg body wt) increased food intake in Nav1.8/LepRfl/fl mice but not in wild-type controls. Ovarian steroidogenesis was suppressed, resulting in decreased plasma estradiol, which was accompanied by decreased expression of estrogen receptor-1 (Esr1) in VAN but not in the hypothalamic arcuate nucleus. These data suggest that the absence of leptin signaling in VAN is accompanied by disruption of estrogen signaling in female mice, leading to an obese phenotype possibly via altered control of feeding behavior.

Chronic refined low-fat diet consumption reduces cholecystokinin satiation in rats.

PURPOSE: Reduced ability of cholecystokinin (CCK) to induce satiation contributes to hyperphagia and weight gain in high-fat/high-sucrose (HF/HS) diet-induced obesity, and has been linked to altered gut microbiota. Rodent models of obesity use chow or low-fat (LF) diets as control diets; the latter has been shown to alter gut microbiota and metabolome. We aimed to determine whether LF-diet consumption impacts CCK satiation in rats and if so, whether this is prevented by addition of inulin to LF diet. METHODS: Rats (n = 40) were fed, for 8 weeks, a chow diet (chow) or low-fat (10%) or high-fat/high-sucrose (45 and 17%, respectively) refined diets with either 10% cellulose (LF and HF/HS) or 10% inulin (LF-I and HF/HS-I). Caecal metabolome was assessed by 1H-NMR-based metabolomics. CCK satiation was evaluated by measuring the suppression of food intake after intraperitoneal CCK injection (1 or 3 µg/kg). RESULTS: LF-diet consumption altered the caecal metabolome, reduced caecal weight, and increased IAP activity, compared to chow. CCK-induced inhibition of food intake was abolished in LF diet-fed rats compared to chow-fed rats, while HF/HS diet-fed rats responded only to the highest CCK dose. Inulin substitution ameliorated caecal atrophy, reduced IAP activity, and modulated caecal metabolome, but did not improve CCK-induced satiety in either LF- or HF/HS-fed rats. CONCLUSIONS: CCK signaling is impaired by LF-diet consumption, highlighting that caution must be taken when using LF diet until a more suitable refined control diet is identified.

Prebiotic milk oligosaccharides prevent development of obese phenotype, impairment of gut permeability, and microbial dysbiosis in high fat-fed mice.

Microbial dysbiosis and increased intestinal permeability are targets for prevention or reversal of weight gain in high-fat (HF) diet-induced obesity (DIO). Prebiotic milk oligosaccharides (MO) have been shown to benefit the host intestine but have not been used in DIO. We hypothesized that supplementation with bovine MO would prevent the deleterious effect of HF diet on the gut microbiota and intestinal permeability and attenuate development of the obese phenotype. C57BL/6 mice were fed a control diet, HF (40% fat/kcal), or HF + prebiotic [6%/kg bovine milk oligosaccharides (BMO) or inulin] for 1, 3, or 6 wk. Gut microbiota and intestinal permeability were assessed in the ileum, cecum, and colon. Addition of BMO to the HF diet significantly attenuated weight gain, decreased adiposity, and decreased caloric intake; inulin supplementation also lowered weight gain and adiposity, but this did not reach significance. BMO and inulin completely abolished the HF diet-induced increase in paracellular and transcellular permeability in the small and large intestine. Both BMO and inulin increased abundance of beneficial microbes Bifidobacterium and Lactobacillus in the ileum. However, inulin supplementation altered phylogenetic diversity and decreased species richness. We conclude that addition of BMO to the HF diet completely prevented increases in intestinal permeability and microbial dysbiosis and was partially effective to prevent weight gain in DIO.NEW & NOTEWORTHY This study provides the first report of the effects of prebiotic bovine milk oligosaccharides on the host phenotype of high-fat diet-induced obesity in mice.

Glucagon-like peptide 1 interacts with ghrelin and leptin to regulate glucose metabolism and food intake through vagal afferent neuron signaling.

Emerging evidence has suggested a possible physiologic role for peripheral glucagon-like peptide 1 (GLP-1) in regulating glucose metabolism and food intake. The likely site of action of GLP-1 is on vagal afferent neurons (VANs). The vagal afferent pathway is the major neural pathway by which information about ingested nutrients reaches the central nervous system and influences feeding behavior. Peripheral GLP-1 acts on VANs to inhibit food intake. The mechanism of the GLP-1 receptor (GLP-1R) is unlike other gut-derived receptors; GLP-1Rs change their cellular localization according to feeding status rather than their protein concentrations. It is possible that several gut peptides are involved in mediating GLP-1R translocation. The mechanism of peripheral GLP-1R translocation still needs to be elucidated. We review data supporting the role of peripheral GLP-1 acting on VANs in influencing glucose homeostasis and feeding behavior. We highlight evidence demonstrating that GLP-1 interacts with ghrelin and leptin to induce satiation. Our aim was to understand the mechanism of peripheral GLP-1 in the development of noninvasive antiobesity treatments.

Deletion of leptin signaling in vagal afferent neurons results in hyperphagia and obesity.

The vagal afferent pathway senses hormones released from the gut in response to nutritional cues and relays these signals to the brain. We tested the hypothesis that leptin resistance in vagal afferent neurons (VAN) is responsible for the onset of hyperphagia by developing a novel conditional knockout mouse to delete leptin receptor selectively in sensory neurons (Nav1.8/LepR (fl/fl) mice). Chow fed Nav1.8/LepR (fl/fl) mice weighed significantly more and had increased adiposity compared with wildtype mice. Cumulative food intake, meal size, and meal duration in the dark phase were increased in Nav1.8/LepR (fl/fl) mice; energy expenditure was unaltered. Reduced satiation in Nav1.8/LepR (fl/fl) mice is in part due to reduced sensitivity of VAN to CCK and the subsequent loss of VAN plasticity. Crucially Nav1.8/LepR (l/fl) mice did not gain further weight in response to a high fat diet. We conclude that disruption of leptin signaling in VAN is sufficient and necessary to promote hyperphagia and obesity.

Ability of GLP-1 to decrease food intake is dependent on nutritional status.

UNLABELLED: Gut-derived glucagon like peptide-1 (GLP-1) acts in the postprandial period to stimulate insulin secretion and inhibit gastrointestinal motor and secretory function; whether endogenous peripheral GLP-1 inhibits food intake is less clear. We hypothesized that GLP-1 inhibits food intake in the fed, but not fasted, state. There is evidence that GLP-1 acts via stimulation of vagal afferent neurons (VAN); we further hypothesized that the satiating effects of endogenous GLP-1 in the postprandial period is determined either by a change in GLP-1 receptor (GLP-1R) expression or localization to different cellular compartments in VAN. METHODS: Food intake was recorded following administration of GLP-1 (50µg/kg or 100µg/kg) or saline (IP) in Wistar rats fasted for 18h or fasted then re-fed with 3g chow. GLP-1R protein expression and localization on VAN were determined by immunocytochemistry and immunoblots in animals fasted for 18h or fasted then re-fed for 40min. GLP-1R mRNA level was detected in animals fasted for 18h or fasted and re-fed ad libitum for 2h. RESULTS: GLP-1 (100µg/kg) significantly reduced 40min food intake by 38% in re-fed but not fasted rats (p<0.05). GLP-1R mRNA or protein levels in VAN were unchanged in re-fed compared to fasted rats. However, GLP-1R localization to the plasma membrane was significantly increased in VAN by feeding. CONCLUSION: Feeding changes the ability of peripheral GLP-1 to inhibit food intake. GLP-1Rs are trafficked to the plasma membrane in response to a meal. GLP-1 may play a role in regulating food intake in the postprandial period.