The intestine is a major contributor to circulating succinate in mice.

The tricarboxylic acid (TCA) cycle is the epicenter of cellular aerobic metabolism. TCA cycle intermediates facilitate energy production and provide anabolic precursors, but also function as intra- and extracellular metabolic signals regulating pleiotropic biological processes. Despite the importance of circulating TCA cycle metabolites as signaling molecules, the source of circulating TCA cycle intermediates remains uncertain. We observe that in mice, the concentration of TCA cycle intermediates in the portal blood exceeds that in tail blood indicating that the gut is a major contributor to circulating TCA cycle metabolites. With a focus on succinate as a representative of a TCA cycle intermediate with signaling activities and using a combination of gut microbiota depletion mouse models and isotopomer tracing, we demonstrate that intestinal microbiota is not a major contributor to circulating succinate. Moreover, we demonstrate that endogenous succinate production is markedly higher than intestinal succinate absorption in normal physiological conditions. Altogether, these results indicate that endogenous succinate production within the intestinal tissue is a major physiological source of circulating succinate. These results provide a foundation for an investigation into the role of the intestine in regulating circulating TCA cycle metabolites and their potential signaling effects on health and disease.

HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis.

Carbohydrate response element-binding protein (ChREBP) is a carbohydrate-sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-Seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified hepatocyte growth factor activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone hepatocyte growth factor. We demonstrate that HGFAC-KO mice had phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhanced lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediated an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.

A two-injection prostaglandin F2α presynchronization treatment decreases pregnancy rates of cycling replacement beef heifers.

Improving artificial insemination (AI) pregnancy rates in replacement heifers improves the genetic advancement within a herd. Heifers that have completed at least three estrous cycles prior to breeding have greater pregnancy rates compared to acyclic females. Therefore, it was hypothesized that a presynchronization treatment program consisting of two injections of prostaglandin F2α (PGF2α) prior to the start of the CO-Synch + 5 d CIDR protocol would initiate earlier attainment of puberty and more estrous cycles prior to AI, thus increasing AI pregnancy rates. All heifers were managed the same at two locations over the course of 2 yr. Heifers were randomly assigned to receive either the two-injection PGF2α presynchronization treatment (PreSynch; n = 105) or no presynchronization (Control; n = 106) prior to the start of estrous synchronization. On the first day of the trial, reproductive tract scores (RTSs), pelvic areas, body condition scores, and weights were collected on all heifers. All heifers were synchronized with the CO-Synch + 5 d CIDR protocol and fixed-time artificially inseminated with semen from a bull of known fertility. Blood samples were collected three consecutive times at 7 d intervals starting 45 d prior to estrous synchronization to determine the onset of puberty via analyzing progesterone concentrations. Pregnancy status to AI was assessed using ultrasonography diagnosis at approximately 30 and 60 d post insemination. Data were analyzed using PROC MIXED of SAS and reported as least square mean. The PreSynch treatment decreased AI pregnancy rates (52.2% vs. 38.1 ± 6.3% for Control vs. PreSynch, respectively; P = 0.06) and did not result in earlier attainment of puberty in beef heifers (P > 0.05). The PreSynch treatment did not impact pregnancy rates in heifers with an RTS of 3 or 4 (P > 0.05). However, PreSynch heifers with an RTS of 5 had decreased pregnancy rates (68.3% vs. 46.9 ± 10.1% for Control vs. PreSynch, respectively; P < 0.05). Finally, PreSynch heifers with increased body condition of 6 had decreased pregnancy rates when compared to Control heifers (37.5% vs. 62.5 ± 11.6%, respectively; P < 0.05). On the basis of these data, implementation of heifer breeding soundness examination at least 3 wk prior to the start of the breeding season may be beneficial for selecting replacement females; however, presynchronization with prostaglandins immediately prior to estrous synchronization will negatively affect AI pregnancy rates in cycling pubertal heifers.