The role of GPR109a signaling in niacin induced effects on fed and fasted hepatic metabolism

Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wild-type (+/+) and knockout (−/−) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16 h fasted) concentrations of the endogenous ligand, β-OH butyrate. In the fed state, niacin increased expression of apolipoprotein-A1 mRNA and decreased sterol regulatory element-binding protein 1 mRNA independent of genotype, suggesting a possible GPR109a independent mechanism by which niacin increases high-density lipoprotein (HDL) production and limits transcriptional upregulation of lipogenic genes. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and −/− mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator-activated receptor α mRNA expression. Although unaffected by niacin treatment, fasting serum HDL concentrations were lower in GPR109a knockout mice. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the fasting ketogenic state or the acute effects of niacin. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity. © 2021Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release

Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity. © 2021Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Characterization of biological types of cattle: indicator traits offertility in beef cows

Genetic diversity among breeds of cattle allows producers to select animals for specific environments or market conditions. Reproductive efficiency is a multi-component trait that is largely influenced by environmental influences such as health and nutritional status; however, there are clearly genetic components to reproductive efficiency, and breed differences in a number of indicator traits associated with fertility and cow productivity have been identified. Historical indicators of fertility include scrotal circumference, age at puberty, and postpartum interval. Both age at puberty and postpartum interval are laborious traits to collect in heifers and cows because they require many days of detection of behavioral estrus. In recent years, the addition of ultrasonography to management practices has allowed for the collection of female traits such as follicle diameter, antral follicle counts, and fetal age that are not as labor intensive. These additional diagnostic traits provide novel phenotypes for the identification of genetic markers of fertility and cow productivity, which would be the ultimate goal. Genetic markers of the number of follicles in the bovine ovary have the potential to identify heifers that will be highly productive cows. Furthermore, identifying and understanding the genes that control various reproductive traits and the response to stressors, such as temperature and nutrient availability, could improve production efficiency by improving management and breeding decisions in a wide range of production environments

Desempenho reprodutivo, características do pelame e taxa de sudação em vacas da raça Braford Effects of hair coat traits and sweating rate on reproductive performance of Braford cows

Foram investigados os efeitos das características do pelame e da taxa de sudação (TS) sobre o intervalo de partos (IEP, n = 423) e os dias para o parto (DPP, n = 1.202) de vacas da raça Braford criadas em sistema extensivo em região tropical úmida no Mato Grosso do Sul, Brasil. As análises foram realizadas pelo método dos quadrados mínimos considerando para intervalo de partos os seguintes efeitos das classes de idade da vaca ao parto: grupo genético; pai; e regressão sobre a refletância da superfície da capa (R), a espessura da capa (E), o comprimento dos pêlos (C), o número de pêlos por unidade de área (N), o diâmetro dos pêlos (D) e a taxa de sudação. Para dias para o parto, foram considerados os efeitos: R, E, C, N, D, TS, divididos em classes; grupo genético; idade no início da estação de monta; e pai. Os componentes de variância e co-variância foram estimados pelo método de Máxima Verossimilhança Restrita sob o modelo touro. As características adaptativas não foram importantes para a variação do intervalo de parto e dos dias para o parto, mas a taxa de sudação apresentou efeito importante sobre dias ao parto. As estimativas de herdabilidade foram quase nulas para IEP e DPP e maiores para as características adaptativas (E = 0,16 ± 0,09; C = 0,18 ± 0,09; N = 0,08 ± 0,06; D = 0,12 ± 0,07; R = 0,30 ± 0,12; TS = 0,10 ± 0,06). Os resultados obtidos para as correlações genéticas de IEP e DPP com TS e entre as características do pelame indicaram que a seleção simultânea para menores valores de C pode ser favorável à redução do intervalo de partos. Em geral, as correlações genéticas entre TS, IEP e DPP apresentaram elevado erro-padrão. Considerando os resultados deste estudo e a importância das características do pelame e da sudação, confirma-se a necessidade de se estudarem as correlações genéticas entre as características adaptativas e o desempenho reprodutivo para o progresso da adaptação de bovinos da raça Braford no Brasil.<br>This study aimed to evaluate the effects of hair coat traits (thickness (T), reflectance (R), length (L), diameter (D) and number of hairs per unit area (N)) and sweating rate (SR) on calving interval (CI, n = 423) and days to calving (DC, n = 1202) of Braford cows raised in Mato Grosso do Sul State, Brazil. Data were analyzed by least squares and the model for CI included the effects of age class of cow, genetic group, sire and regression on R, T, L, N, D and SR. For days to calving the following effects were considered: R, T, L, N, D, TS divided in classes; regressions on genetic group, age at the beginning of breeding season and sire. Variance and covariance components were estimated by REML. Hair coat traits and SR traits were not statistically significant for CI, but the SR effect was statistically significant on DC. The heritability estimates were practically null for CI and DC and ranged from 0.08 to 0.30 for adaptive characteristics (T = 0.16 ± 0.09; L = 0.18 ± 0.09; N = 0.08 ± 0.06; D = 0.12 ± 0.07; R = 0.30 ± 0.12; SR = 0.10 ± 0.06). Overall, estimates of genetic correlations between pair of traits (hair coat, sweating rate, CI and DC) were characterized by high standard errors. Additional data is required to obtain accurate estimates of genetic correlations among hair coat traits, sweating rate and reproductive performance of Braford cows in Brazil