It is well established that food intake behavior and energy balance are regulated by crosstalk between peripheral organ systems and the central nervous system (CNS), for instance, through the actions of peripherally derived leptin on hindbrain and hypothalamic loci. Diet- or obesity-associated disturbances in metabolic and hormonal signals to the CNS can perturb metabolic homeostasis bodywide. Although interrelations between metabolic status and diet with CNS biology are well characterized, afferent networks (those sending information to the CNS from the periphery) have received far less attention. It is increasingly appreciated that afferent neurons in adipose tissue, the intestines, liver, and other tissues are important controllers of energy balance and feeding behavior. Disruption in their signaling may have consequences for cardiovascular, pancreatic, adipose, and immune function. This review discusses the diverse ways that afferent neurons participate in metabolic homeostasis and highlights how changes in their function associate with dysmetabolic states, such as obesity and insulin resistance.

Abstract Background High dietary calcium (Ca) is reported to have anti-obesity and anti-inflammatory properties. Evidence for these properties of dietary Ca in animal models of polygenic obesity have been confounded by the inclusion of dairy food components in experimental diets; thus, effect of Ca per se could not be deciphered. Furthermore, potential anti-inflammatory actions of Ca in vivo could not be dissociated from reduced adiposity. Methods We characterized adiposity along with metabolic and inflammatory phenotypes in diet-induced obese (DIO) mice fed 1 of 3 high fat diets (45% energy) for 12 wk: control (n = 29), high-Ca (n = 30), or high-Ca + nonfat dry milk (NFDM) (n = 30). Results Mice fed high-Ca + NFDM had reduced body weight and adiposity compared to high-Ca mice (P < 0.001). Surprisingly, the high-Ca mice had increased adiposity compared to lower-Ca controls (P < 0.001). Hyperphagia and increased feed efficiency contributed to obesity development in high-Ca mice, in contrast to NFDM mice that displayed significantly reduced weight gain despite higher energy intake compared to controls (P < 0.001). mRNA markers of macrophages (e.g., CD68, CD11d) strongly correlated with body weight in all diet treatment groups, and most treatment differences in WAT inflammatory factor mRNA abundances were lost when controlling for body weight gain as a covariate. Conclusions The results indicate that high dietary Ca is not sufficient to dampen obesity-related phenotypes in DIO mice, and in fact exacerbates weight gain and hyperphagia. The data further suggest that putative anti-obesity properties of dairy emanate from food components beyond Ca.

Background

Diets rich in dairy and/or calcium (Ca) have been associated with reductions in adiposity and inflammation, but the mechanisms underlying this remain to be fully elucidated. Oxylipins and endocannabinoids are bioactive lipids, which influence energy homeostasis, adipose function, insulin signaling, and inflammation. Our objective was to determine if these metabolites associate with metabolic and inflammatory phenotypes stemming from dietary Ca and dairy in diet induced obese mice.

Methods

In one study, C57BL6/J mice were fed high fat diets (45% energy) with varying dietary matrices for 12 weeks: soy protein and Ca adequate (0.5%; CONTROL), soy protein and high Ca (1.5%; HighCa), or nonfat-dry-milk based high Ca (NFDM). In a second study, mice were pre-fattened for 12 weeks on the CONTROL high fat diet, and then fed one of three high fat diets for an additional 8 weeks: CONTROL, HighCa, or NFDM. In both studies, adiposity and associated metabolic and inflammatory outcomes were measured and a targeted lipidomics analysis was performed on plasma collected during the post-absorptive condition.

Results

As reported previously, mice fed NFDM had less body fat and reduced mRNA markers of adipose inflammation (p < 0.05) than CONTROL mice despite greater cumulative energy intake. Moreover, NFDM fed mice lipid mediator profiles were distinct from CONTROL and HighCa mice. NFDM fed mice showed elevated plasma monoacylglycerols (6 - 46% increase from CONTROL), including 2-arachidonoylglycerol (2-AG), and reduced fatty acid diols (8-75% decrease from CONTROL).

Conclusions

Differences in specific plasma lipid mediator profiles reflect the metabolic and inflammatory phenotypes seen in NFDM feeding.

Introduction

Names are a reflection of identity and often have personal meaning. The chronic mispronunciation of names can undermine one's identity and be experienced as a microaggression. This workshop aims to provide historical context for names as well as resources for correct name pronunciation.

Methods

We developed a 60-minute interactive virtual workshop with didactics, small-group sharing of personal experiences, and case discussions. We used an anonymous postworkshop survey to evaluate workshop effectiveness.

Results

We presented the workshop at one local academic conference and two local educational conferences to learners of all levels from medical students to faculty. We collected postworkshop survey results from 78 participants of diverse racial and ethnic backgrounds. Participants reported learning historical context, ways to ask about correct name pronunciation, correcting name mispronunciation, documenting pronunciation, and sources for applications to practice. The main barriers to implementing workshop lessons included personal and structural factors.

Discussion

This workshop effectively fills an educational gap by addressing the importance of correct name pronunciation in order to provide a more inclusive environment for clinicians and patients alike.

Recent evidence in adipocytes points to a role for synuclein-γ in metabolism and lipid droplet dynamics, but interestingly this factor is also robustly expressed in peripheral neurons. Specific regulation of the synuclein-γ gene (Sncg) by PPARγ requires further evaluation, especially in peripheral neurons, prompting us to test if Sncg is a bona fide PPARγ target in murine adipocytes and peripheral somatosensory neurons derived from the dorsal root ganglia (DRG). Sncg mRNA was decreased in 3T3-L1 adipocytes (~68%) by rosiglitazone, and this effect was diminished by the PPARγ antagonist T0070907. Chromatin immunoprecipitation experiments confirmed PPARγ protein binding at two promoter sequences of Sncg during 3T3-L1 adipogenesis. Rosiglitazone did not affect Sncg mRNA expression in murine cultured DRG neurons. In subcutaneous human WAT samples from two cohorts treated with pioglitazone (>11 wks), SNCG mRNA expression was reduced, albeit highly variable and most evident in type 2 diabetes. Leptin (Lep) expression, thought to be coordinately-regulated with Sncg based on correlations in human adipose tissue, was also reduced in 3T3-L1 adipocytes by rosiglitazone. However, Lep was unaffected by PPARγ antagonist, and the LXR agonist T0901317 significantly reduced Lep expression (~64%) while not impacting Sncg. The results support the concept that synuclein-γ shares some, but not all, gene regulators with leptin and is a PPARγ target in adipocytes but not DRG neurons. Regulation of synuclein-γ by cues such as PPARγ agonism in adipocytes is logical based on recent evidence for an important role for synuclein-γ in the maintenance and dynamics of adipocyte lipid droplets.

Background

High-amylose-maize resistant starch type 2 (HAMRS2) is a fermentable dietary fiber known to alter the gut milieu, including the gut microbiota, which may explain the reported effects of resistant starch to ameliorate obesity-associated metabolic dysfunction.

Objective

Our working hypothesis was that HAMRS2-induced microbiome changes alter gut-derived signals (i.e., xenometabolites) reaching the liver via the portal circulation, in turn altering liver metabolism by regulating gene expression and other pathways.

Methods

We used a multi-omics systems biology approach to characterize HAMRS2-driven shifts to the cecal microbiome, liver metabolome, and transcriptome, identifying correlates between microbial changes and liver metabolites under obesogenic conditions that, to our knowledge, have not previously been recognized. Five-week-old male C57BL/6J mice were fed an energy-dense 45% lard-based-fat diet for 10 wk supplemented with either 20% HAMRS2 by weight (n = 14) or rapidly digestible starch (control diet; n = 15).

Results

Despite no differences in food intake, body weight, glucose tolerance, fasting plasma insulin, or liver triglycerides, the HAMRS2 mice showed a 15-58% reduction in all measured liver amino acids, except for Gln, compared with control mice. These metabolites were equivalent in the plasma of HAMRS2 mice compared with controls, and transcripts encoding key amino acid transporters were not different in the small intestine or liver, suggesting that HAMRS2 effects were not simply due to lower hepatocyte exposure to systemic amino acids. Instead, alterations in gut microbial metabolism could have affected host nitrogen and amino acid homeostasis: HAMRS2 mice showed a 62% increase (P < 0.0001) in 48-h fecal output and a 41% increase (P < 0.0001) in fecal nitrogen compared with control mice. Beyond amino acid metabolism, liver transcriptomics revealed pathways related to lipid and xenobiotic metabolism; and pathways related to cell proliferation, differentiation, and growth were affected by HAMRS2 feeding.

Conclusion

Together, these differences indicate that HAMRS2 dramatically alters hepatic metabolism and gene expression concurrent with shifts in specific gut bacteria in C57BL/6J mice.

Background

Enzyme-treated wheat bran (ETWB) contains a fermentable dietary fiber previously shown to decrease liver triglycerides (TGs) and modify the gut microbiome in mice. It is not clear which mechanisms explain how ETWB feeding affects hepatic metabolism, but factors (i.e., xenometabolites) associated with specific microbes may be involved.

Objective

The objective of this study was to characterize ETWB-driven shifts in the cecal microbiome and to identify correlates between microbial changes and diet-related differences in liver metabolism in diet-induced obese mice that typically display steatosis.

Methods

Five-week-old male C57BL/6J mice fed a 45%-lard-based fat diet supplemented with ETWB (20% wt:wt) or rapidly digestible starch (control) (n = 15/group) for 10 wk were characterized by using a multi-omics approach. Multivariate statistical analysis was used to identify variables that were strong discriminators between the ETWB and control groups.

Results

Body weight and liver TGs were decreased by ETWB feeding (by 10% and 25%, respectively; P < 0.001), and an index of liver reactive oxygen species was increased (by 29%; P < 0.01). The cecal microbiome showed an increase in Bacteroidetes (by 42%; P < 0.05) and a decrease in Firmicutes (by 16%; P < 0.05). Metabolites that were strong discriminators between the ETWB and control groups included decreased liver antioxidants (glutathione and α-tocopherol); decreased liver carbohydrate metabolites, including glucose; lower hepatic arachidonic acid; and increased liver and plasma β-hydroxybutyrate. Liver transcriptomics revealed key metabolic pathways affected by ETWB, especially those related to lipid metabolism and some fed- or fasting-regulated genes.

Conclusions

Together, these changes indicate that dietary fibers such as ETWB regulate hepatic metabolism concurrently with specific gut bacteria community shifts in C57BL/6J mice. It is proposed that these changes may elicit gut-derived signals that reach the liver via enterohepatic circulation, ultimately affecting host liver metabolism in a manner that mimics, in part, the fasting state.

Context

Compared with glucose-sweetened beverages, consumption of fructose-sweetened beverages with meals elevates postprandial plasma triglycerides and lowers 24-h insulin and leptin profiles in normal-weight women. The effects of fructose, compared with glucose, ingestion on metabolic profiles in obese subjects has not been studied.

Objective

The objective of the study was to compare the effects of fructose- and glucose-sweetened beverages consumed with meals on hormones and metabolic substrates in obese subjects.

Design and setting

The study had a within-subject design conducted in the clinical and translational research center.

Participants

Participants included 17 obese men (n = 9) and women (n = 8), with a body mass index greater than 30 kg/m(2).

Interventions

Subjects were studied under two conditions involving ingestion of mixed nutrient meals with either glucose-sweetened beverages or fructose-sweetened beverages. The beverages provided 30% of total kilocalories. Blood samples were collected over 24 h.

Main outcome measures

Area under the curve (24 h AUC) for glucose, lactate, insulin, leptin, ghrelin, uric acid, triglycerides (TGs), and free fatty acids was measured.

Results

Compared with glucose-sweetened beverages, fructose consumption was associated with lower AUCs for insulin (1052.6 +/- 135.1 vs. 549.2 +/- 79.7 muU/ml per 23 h, P < 0.001) and leptin (151.9 +/- 22.7 vs. 107.0 +/- 15.0 ng/ml per 24 h, P < 0.03) and increased AUC for TG (242.3 +/- 96.8 vs. 704.3 +/- 124.4 mg/dl per 24 h, P < 0.0001). Insulin-resistant subjects exhibited larger 24-h TG profiles (P < 0.03).

Conclusions

In obese subjects, consumption of fructose-sweetened beverages with meals was associated with less insulin secretion, blunted diurnal leptin profiles, and increased postprandial TG concentrations compared with glucose consumption. Increases of TGs were augmented in obese subjects with insulin resistance, suggesting that fructose consumption may exacerbate an already adverse metabolic profile present in many obese subjects.