Although the developing pancreas is exquisitely sensitive to nutrient supply in utero, it is not entirely clear how nutrient-driven posttranslational modification of proteins impacts the pancreas during development. We hypothesized that the nutrient-sensing enzyme O-GlcNAc transferase (Ogt), which catalyzes an O-GlcNAc-modification onto key target proteins, integrates nutrient-signaling networks to regulate cell survival and development. In this study, we investigated the heretofore unknown role of Ogt in exocrine and endocrine islet development. By genetic manipulation in vivo and by using morphometric and molecular analyses, such as immunofluorescence imaging and single cell RNA sequencing, we show the first evidence that Ogt regulates pancreas development. Genetic deletion of Ogt in the pancreatic epithelium (OgtKO Panc) causes pancreatic hypoplasia, in part by increased apoptosis and reduced levels of of Pdx1 protein. Transcriptomic analysis of single cell and bulk RNA sequencing uncovered cell-type heterogeneity and predicted upstream regulator proteins that mediate cell survival, including Pdx1, Ptf1a and p53, which are putative Ogt targets. In conclusion, these findings underscore the requirement of O-GlcNAcylation during pancreas development and show that Ogt is essential for pancreatic progenitor survival, providing a novel mechanistic link between nutrients and pancreas development.

Obesity is characterized by chronic low-grade inflammation that could lead to other health complications, such as cardiovascular disease, diabetes, and various forms of cancer. Emerging evidence has shown that taste perception is altered during the development of obesity. Moreover, suppression of taste receptor or taste signaling molecules potentiate the inflammatory response, and the progression of inflammation attenuates the expression of taste receptors in vivo. Together, these findings suggest a possible interplay between taste signaling and inflammation. This review summarizes the interactions between type 1 (T1Rs) and type 2 taste receptors (T2Rs) and inflammation, as well as the impact of obesity on T1R- and T2R-mediated signaling. Furthermore, we evaluate the possible role that taste receptors play in regulating the inflammatory response during obesity as a therapeutic target to prevent the progression of comorbidities associated with obesity.

ABSTRACT Background Whole egg (WE) consumption has been demonstrated to attenuate body weight (BW) gain and adiposity in genetic animal models of type 2 diabetes (T2D). This finding was accompanied by increased food consumption. Objectives This study aimed to examine the effects of long-term WE intake on BW gain, fat distribution, and food intake in a rat model of diet-induced obesity (DIO). Methods Male Sprague Dawley rats (n = 24) were obtained at 5 wk of age and were randomly weight-matched across 1 of 4 dietary intervention groups (6 rats per group): a casein-based diet (CAS), a high-fat high-sucrose CAS diet (HFHS CAS), a whole egg–based diet (EGG), or a high-fat high-sucrose EGG diet (HFHS EGG). All diets provided 20% (w/w) protein and were provided for 33 wk. HFHS diets provided ∼61% of kilocalories from fat and 10% from sucrose. Daily weight gain and food intake were recorded, biochemical parameters were measured via ELISA, and epididymal fat pad weights were recorded at the end of the study. Results At 33 wk, cumulative BW gain in DIO rats fed HFHS EGG resulted in 23% lower weight gain compared with DIO rats fed HFHS CAS (P < 0.0001), but no significant differences in BW gain were observed between the HFHS EGG group and the control EGG and CAS groups (P = 0.71 and P = 0.61, respectively). Relative food intake (grams per kilogram BW) was 23% lower (P < 0.0001) in rats fed HFHS CAS compared with CAS, whereas there was no difference in food intake within the EGG dietary groups. DIO rats fed HFHS EGG exhibited a 22% decrease in epididymal fat weight compared with their counterparts fed the HFHS CAS. Conclusions Our data demonstrate that consumption of a WE-based diet reduced BW gain and visceral fat in the DIO rat, similar to our previous findings in a genetic rat model with T2D.

Protein O-GlcNAcylation is a nutrient and stress-sensitive protein post-translational modification (PTM). The addition of an O-GlcNAc molecule to proteins is catalyzed by O-GlcNAc transferase (OGT), whereas O-GlcNAcase (OGA) enzyme is responsible for removal of this PTM. Previous work showed that OGT is highly expressed in the pancreas, and we demonstrated that hypo-O-GlcNAcylation in β-cells cause severe diabetes in mice. These studies show a direct link between nutrient-sensitive OGT and β-cell health and function. In the current study, we hypothesized that hyper-O-GlcNAcylation may confer protection from β-cell failure in high-fat diet (HFD)-induced obesity. To test this hypothesis, we generated a mouse model with constitutive β-cell OGA ablation (βOGAKO) to specifically increase O-GlcNAcylation in β-cells. Under normal chow diet, young male and female βOGAKO mice exhibited normal glucose tolerance but developed glucose intolerance with aging, relative to littermate controls. No alteration in β-cell mass was observed between βOGAKO and littermate controls. Total insulin content was reduced despite an increase in pro-insulin to insulin ratio in βOGAKO islets. βOGAKO mice showed deficit in insulin secretion in vivo and in vitro. When young animals were subjected to HFD, both male and female βOGAKO mice displayed normal body weight gain and insulin tolerance but developed glucose intolerance that worsened with longer exposure to HFD. Comparable β-cell mass was found between βOGAKO and littermate controls. Taken together, these data demonstrate that the loss of OGA in β-cells reduces β-cell function, thereby perturbing glucose homeostasis. The findings reinforce the rheostat model of intracellular O-GlcNAcylation where too much (OGA loss) or too little (OGT loss) O-GlcNAcylation are both detrimental to the β-cell.

Background Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 10% of reproductive-aged women and leads to hyperandrogenism, anovulation, and infertility. PCOS has been associated with elevated serum homocysteine as well as altered methylation status; however, characterization of one-carbon metabolism (OCM) in PCOS remains incomplete. Objectives The aim of our research was to assess OCM in a letrozole-induced Sprague Dawley rat model of PCOS. Methods Five-week-old female rats (n = 36) were randomly assigned to letrozole [0.9 mg/kg body weight (BW)] treatment or vehicle (carboxymethylcellulose) control that was administered via subcutaneously implanted slow-release pellets every 30 d. For both treatment groups, 12 rats were randomly assigned to be euthanized during proestrus at one of the following time points: 8, 16, or 24 wk of age. Daily BW was measured and estrous cyclicity was monitored during the last 30 d of the experimental period. Ovaries were collected to assess mRNA and protein abundance of OCM enzymes. Results Letrozole-induced rats exhibited 1.9-fold higher cumulative BW gain compared with control rats across all age groups (P < 0.0001). Letrozole reduced the time spent at proestrus (P = 0.0001) and increased time in metestrus (P < 0.0001) of the estrous cycle. Cystathionine β-synthase (Cbs) mRNA abundance was reduced in the letrozole-induced rats at 16 (59%; P < 0.05) and 24 (77%; P < 0.01) wk of age. In addition, CBS protein abundance was 32% lower in 8-wk-old letrozole-induced rats (P = 0.02). Interestingly, betaine-homocysteine S-methyltransferase mRNA abundance increased as a function of age in letrozole-induced rats (P = 0.03). Conclusion These data demonstrate that letrozole-induced PCOS Sprague Dawley rats temporally decrease the ovarian abundance of Cbs mRNA and protein in the early stages of PCOS.