Does nutrient sensing determine how we "see" food?

The ability to "see" both incoming and circulating nutrients plays an essential role in the maintenance of energy homeostasis. As such, nutrient-sensing mechanisms in both the gastrointestinal tract and the brain have been implicated in the regulation of energy intake and glucose homeostasis. The intestinal wall is able to differentiate individual nutrients through sensory machinery expressed in the mucosa and provide feedback signals, via local gut peptide action, to maintain energy balance. Furthermore, both the hypothalamus and hindbrain detect circulating nutrients and respond by controlling energy intake and glucose levels. Conversely, nutrient sensing in the intestine plays a role in stimulating food intake and preferences. In this review, we highlight the emerging evidence for the regulation of energy balance through nutrient-sensing mechanisms in the intestine and the brain, and how disruption of these pathways could result in the development of obesity and type 2 diabetes.

Preserved adiposity in the Fischer 344 rat devoid of gut microbiota.

The gut microbiota is implicated in host metabolism and energy regulation. Germ-free (GF) C57BL/6 mice display decreased adiposity, an effect associated with increased intestinal fasting-induced adipose factor (FIAF) and decreased hepatic lipogenesis. However, whether the altered metabolism observed in the absence of gut microbiota extends to other species, commonly used to examine energy metabolism, is unknown. Thus, we used the GF Fischer 344 rat to examine adiposity and associated alterations in intestinal nutrient chemoreceptors, gut peptide levels, and FIAF expression, as well as markers of hepatic and adipose lipogenesis and adipogenesis. We found that GF rats displayed similar body weights and adiposity relative to controls. GF state was associated with up-regulation of intestinal and hepatic FIAF, decreased expression of hepatic FAS, ACC-1, and SREBP, and increased pAMPK and pACC. However, GF rats displayed reduced adipocyte FIAF, increased lipogenic enzymes, and decreased pAMPK, accompanied by an increase in adipocyte size. These findings show that, despite increased intestinal FIAF and reduced hepatic lipogenesis, adiposity is preserved in the Fisher 344 GF rat, unlike the C57Bl/6J GF mouse, with a shift in increased adipocyte lipogenesis. This also demonstrates that adipose, rather than intestinal, FIAF may have a more prominent role in adiposity.

Characterization of the Gut Microbiota in Individuals with Overweight or Obesity during a Real-World Weight Loss Dietary Program: A Focus on the Bacteroides 2 Enterotype.

BACKGROUND: Dietary intervention is a cornerstone of weight loss therapies. In obesity, a dysbiotic gut microbiota (GM) is characterized by high levels of Bacteroides lineages and low diversity. We examined the GM composition changes, including the Bacteroides 2 enterotype (Bact2), in a real-world weight loss study in subjects following a high-protein hypocaloric diet with or without a live microorganisms (LMP) supplement. METHOD: 263 volunteers were part of this real-world weight loss program. The first phase was a high-protein low-carbohydrate calorie restriction diet with or without LMP supplements. Fecal samples were obtained at baseline and after 10% weight loss for 163 subjects. Metagenomic profiling was obtained by shotgun sequencing. RESULTS: At baseline, the Bact2 enterotype was more prevalent in subjects with aggravated obesity and metabolic alterations. After weight loss, diversity increased and Bact2 prevalence decreased in subjects with lower GM diversity at baseline, notably in LMP consumers. Significant increases in Akkermansia muciniphila and Parabacteroides distasonis and significant decreases of Eubacterium rectale, Streptococcus thermophilus and Bifidobacterial lineages were observed after weight loss. CONCLUSIONS: Baseline microbiome composition is associated with differential changes in GM diversity and Bact2 enterotype prevalence after weight loss. Examining these signatures could drive future personalized nutrition efforts towards more favorable microbiome compositions.

Reduced sensitivity to cholecystokinin in male rats fed a high-fat diet is reversible.

Adult rats chronically fed a high-fat (HF) diet maintain reduced sensitivity to cholecystokinin (CCK). We hypothesized that, similar to adult rats, pups fed a HF diet would also exhibit reduced sensitivity to CCK. To test this, male pups fed low-fat (LF) and HF isoenergetic (16.2 kJ/g) diets were administered CCK intraperitoneally (0.125-1 microg/kg) 1 wk following dietary adaptation. After receiving 0.5 microg/kg CCK, pups fed the HF diet suppressed food intake less (8.9 +/- 5.0%) than pups fed the LF diet (28.9 +/- 4.7%; P < 0.05) relative to intakes after saline administration. We then assessed the development and extinction of changes in CCK sensitivity by switching the diets between the groups. The HF-fed group, when switched to the LF diet, regained sensitivity by wk 4 and suppressed food intake following administration of 0.25 microg/kg CCK (33.1 +/- 5.7%; P < 0.05). The LF-fed group, when switched to the HF diet, lost sensitivity by wk 2 and did not suppress food intake after administrations of CCK compared with saline. Finally, we examined if HF-fed rats have an increased sensitivity to corn oil during brief access tests using a multibottle gustometer. At oil concentrations of 25, 75, and 100%, rats fed the HF diet sampled more oil than LF-fed rats (P < 0.05). These findings demonstrate that male rat pups fed a HF diet exhibit reduced sensitivity to CCK, the development of this reduced sensitivity is quicker than its extinction, and rats consuming a HF diet have increased oral sensitivity to oils.

Lower resource utilization for patients with healed diabetic foot ulcers during participation in a prevention program with foot temperature monitoring.

INTRODUCTION: We assessed the impact of a diabetic foot ulcer prevention program incorporating once-daily foot temperature monitoring on hospitalizations, emergency department and outpatient visits, and rates of diabetic foot ulcer recurrence and lower extremity amputations for patients with recently healed foot ulcers. RESEARCH DESIGN AND METHODS: In this retrospective analysis of real-world data, we enrolled 80 participants with a healed diabetic foot ulcer in a year-long foot ulcer recurrence prevention program. Four outpatient centers within a large integrated healthcare system in the USA contributed to enrollment. We evaluated diabetic foot-related outcomes and associated resource utilization for participants during three periods: the 2 years before the program, the year during the program, and after the program ended. We reported unadjusted resource utilization rates during the program and the periods before and after it. We then adjusted rates of outcomes in each phase using an interrupted time series approach, explicitly controlling for overall trends in resource utilization and recurrence during the three periods. RESULTS: Our unadjusted data showed high initial rates of resource utilization and recurrence before enrollment in the program, followed by lower rates during the program, and higher rates of resource utilization and similar rates of recurrence in the period following the end of the program. The adjusted data showed lower rates of hospitalizations (relative risk reduction (RRR)=0.52; number needed to treat (NNT)=3.4), lower extremity amputations (RRR=0.71; NNT=6.4), and outpatient visits (RRR=0.26; absolute risk reduction (ARR)=3.5) during the program. We also found lower rates of foot ulcer recurrence during the program in the adjusted data, particularly for wounds with infection or greater than superficial depth (RRR=0.91; NNT=4.4). CONCLUSIONS: We observed lower rates of healthcare resource utilization for high-risk participants during enrollment in a diabetic foot prevention program incorporating once-daily foot temperature monitoring. TRIAL REGISTRATION NUMBER: NCT04345016.

Effect of diet on preference and intake of sucrose in obese prone and resistant rats.

Increased orosensory stimulation from palatable diets and decreased feedback from gut signals have been proposed as contributing factors to obesity development. Whether altered taste functions associated with obesity are common traits or acquired deficits to environmental factors, such as a high-energy (HE)-diet, however, is not clear. To address this, we examined preference and sensitivity of increasing concentrations of sucrose solutions in rats prone (OP) and resistant (OR) to obesity during chow and HE feeding and measured lingual gene expression of the sweet taste receptor T1R3. When chow-fed, OP rats exhibited reduced preference and acceptance of dilute sucrose solutions, sham-fed less sucrose compared to OR rats, and had reduced lingual T1R3 gene expression. HE-feeding abrogated differences in sucrose preference and intake and lingual T1R3 expression between phenotypes. Despite similar sucrose intakes however, OP rats consumed significantly more total calories during 48-h two-bottle testing compared to OR rats. The results demonstrate that OP rats have an innate deficit for sweet taste detection, as illustrated by a reduction in sensitivity to sweets and reduced T1R3 gene expression; however their hyperphagia and subsequent obesity during HE-feeding is most likely not due to altered consumption of sweets.

Increased oral detection, but decreased intestinal signaling for fats in mice lacking gut microbiota.

Germ-free (GF) mice lacking intestinal microbiota are significantly leaner than normal (NORM) control mice despite consuming more calories. The contribution of microbiota on the recognition and intake of fats is not known. Thus, we investigated the preference for, and acceptance of, fat emulsions in GF and NORM mice, and associated changes in lingual and intestinal fatty acid receptors, intestinal peptide content, and plasma levels of gut peptides. GF and NORM C57Bl/6J mice were given 48-h two-bottle access to water and increasing concentrations of intralipid emulsions. Gene expression of the lingual fatty acid translocase CD36 and protein expression of intestinal satiety peptides and fatty-acid receptors from isolated intestinal epithelial cells were determined. Differences in intestinal enteroendocrine cells along the length of the GI tract were quantified. Circulating plasma satiety peptides reflecting adiposity and biochemical parameters of fat metabolism were also examined. GF mice had an increased preference and intake of intralipid relative to NORM mice. This was associated with increased lingual CD36 (P<0.05) and decreased intestinal expression of fatty acid receptors GPR40 (P<0.0001), GPR41 (P<0.0001), GPR43 (P<0.05), and GPR120 (P<0.0001) and satiety peptides CCK (P<0.0001), PYY (P<0.001), and GLP-1 (P<0.001). GF mice had fewer enteroendocrine cells in the ileum (P<0.05), and more in the colon (P<0.05), relative to NORM controls. Finally, GF mice had lower levels of circulating leptin and ghrelin (P<0.001), and altered plasma lipid metabolic markers indicative of energy deficits. Increased preference and caloric intake from fats in GF mice are associated with increased oral receptors for fats coupled with broad and marked decreases in expression of intestinal satiety peptides and fatty-acid receptors.

Blockade of hindbrain NMDA receptors containing NR2 subunits increases sucrose intake.

We have previously shown that blockade of N-methyl-d-aspartate (NMDA) receptors in the caudal brain stem delays satiation and increases food intake. NMDA receptors are heterodimers made up of distinct, but different, ion channel subunits. The NR2 subunits of the NMDA receptor contain the binding site for glutamate. About half of vagal afferents express immunoreactivity for NMDA NR2B subunit and about half of the NR2B expressing afferents also express NMDA NR2C or NR2D subunits. This suggests that increased food intake may be evoked by interference with glutamate binding to NMDA channels containing the NR2B subunit. To test this, we measured deprivation-induced intake of 15% sucrose solution following fourth ventricle and intra-nucleus of the solitary tract (intra-NTS) injections of Conantokin G (Con G; NR2B blocker), d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene; NR2B/2A blocker), and (+/-)-cis-1-(phenanthren-2yl-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA; NR2D/C blocker). Fourth ventricular administration of Con G (5, 20, 40, 80 ng), d-CPPene (3.0, 6.25, 12.5, 25, 50, 100 ng), and PPDA (300, 400 ng) increased sucrose intake significantly compared with control. Likewise, injections of Con G (10 ng), d-CPPene (5 ng, 10 ng), and PPDA (0.5, 1.0, 2.5, 5.0 ng) directly into the NTS significantly increased sucrose intake. These results show that hindbrain injection of competitive NMDA antagonists with selectivity or preference for the NMDA receptor NR2B or NR2C subunits increases food intake.