Coordinated Defects in Hepatic Long Chain Fatty Acid Metabolism and Triglyceride Accumulation Contribute to Insulin Resistance in Non-Human Primates

Kamath, Subhash; Chávez, Alberto O.; Gastaldelli, Amalia; Casiraghi, Francesca; Halff, Glenn A.; Abrahamian, Gregory A; Davalli, Alberto M.; Bastarrachea, Raúl A.; Comuzzie, Anthony G.; Guardado-Mendoza, Rodolfo; Jiménez-Ceja, Lilia M.; Mattern, Vicki; Paez, Ana; Ricotti, Andrea; Tejero, M. Elizabeth; Higgins, Paul; Rodríguez‐Sánchez, Iram P.; Tripathy, Devjit; DeFronzo, Ralph A.; Dick, Edward J.; Cline, Gary W.; Folli, Franco

doi:10.1371/journal.pone.0027617

Cited by 34 publications

(29 citation statements)

References 61 publications

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“…Plasma EC concentrations were measured at baseline, 3.5 wk, and 7 wk, whereas tissue concentrations were measured in biopsy samples taken at baseline and 7 wk. Liver biopsy samples were used to measure liver-TG content, as described previously (32).…”

Section: Methodsmentioning

confidence: 99%

Selective cannabinoid-1 receptor blockade benefits fatty acid and triglyceride metabolism significantly in weight-stable nonhuman primates

Vaidyanathan

Bastarrachea

Higgins

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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The goal of this study was to determine whether administration of the CB₁ cannabinoid receptor antagonist rimonabant would alter fatty acid flux in nonhuman primates. Five adult baboons (Papio Sp) aged 12.1 ± 4.7 yr (body weight: 31.9 ± 2.1 kg) underwent repeated metabolic tests to determine fatty acid and TG flux before and after 7 wk of treatment with rimonabant (15 mg/day). Animals were fed ad libitum diets, and stable isotopes were administered via diet (d₃₁-tripalmitin) and intravenously (¹³C₄-palmitate, ¹³C₁-acetate). Plasma was collected in the fed and fasted states, and blood lipids were analyzed by GC-MS. DEXA was used to assess body composition and a hyperinsulinemic euglycemic clamp used to assess insulin-mediated glucose disposal. During the study, no changes were observed in food intake, body weight, plasma, and tissue endocannabinoid concentrations or the quantity of liver-TG fatty acids originating from de novo lipogenesis (19 ± 6 vs. 16 ± 5%, for pre- and posttreatment, respectively, P = 0.39). However, waist circumference was significantly reduced 4% in the treated animals (P < 0.04), glucose disposal increased 30% (P = 0.03), and FFA turnover increased 37% (P = 0.02). The faster FFA flux was consistent with a 43% reduction in these fatty acids used for TRL-TG synthesis (40 ± 3 vs. 23 ± 4%, P = 0.02) and a twofold increase in TRL-TG turnover (1.5 ± 0.9 vs. 3.1 ± 1.4 μmol·kg⁻¹·h⁻¹, P = 0.03). These data support the potential for a strong effect of CB₁ receptor antagonism at the level of adipose tissue, resulting in improvements in fasting turnover of fatty acids at the whole body level, central adipose storage, and significant improvements in glucose homeostasis.

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Section: Methodsmentioning

confidence: 99%

Selective cannabinoid-1 receptor blockade benefits fatty acid and triglyceride metabolism significantly in weight-stable nonhuman primates

Vaidyanathan

Bastarrachea

Higgins

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…High fat diets (HFD) induce obesity and NAFLD [33,53,55,115,120,124]. However, despite the fact that NAFLD is more prevalent in women [23,24], most HFD-induced rodent models of NAFLD have focused only on males fed HFD ad libitum (rev.…”

Section: Introductionmentioning

confidence: 99%

Ablating both Fabp1 and Scp2/Scpx (TKO) induces hepatic phospholipid and cholesterol accumulation in high fat-fed mice

Milligan

Martin

Landrock

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Although singly ablating Fabp1 or Scp2/Scpx genes may exacerbate the impact of high fat diet (HFD) on whole body phenotype and non-alcoholic fatty liver disease (NAFLD), concomitant upregulation of the non-ablated gene, preference for ad libitum fed HFD, and sex differences complicate interpretation. Therefore, these issues were addressed in male and female mice ablated in both genes (Fabp1/Scp2/Scpx null or TKO) and pair-fed HFD. Wild-type (WT) males gained more body weight as fat tissue mass (FTM) and exhibited higher hepatic lipid accumulation than WT females. The greater hepatic lipid accumulation in WT males was associated with higher hepatic expression of enzymes in glyceride synthesis, higher hepatic bile acids, and upregulation of transporters involved in hepatic reuptake of serum bile acids. While TKO had little effect on whole body phenotype and hepatic bile acid accumulation in either sex, TKO increased hepatic accumulation of lipids in both, specifically phospholipid and cholesteryl esters in males and females and free cholesterol in females. TKO-induced increases in glycerides were attributed not only to complete loss of FABP1, SCP2 and SCPx, but also in part to sex-dependent upregulation of hepatic lipogenic enzymes. These data with WT and TKO mice pair-fed HFD indicate that: i) Sex significantly impacted the ability of HFD to increase body weight, induce hepatic lipid accumulation and increase hepatic bile acids; and ii) TKO exacerbated the HFD ability to induce hepatic lipid accumulation, regardless of sex, but did not significantly alter whole body phenotype in either sex.

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“…These features distinguish baboons from rodents, which are frequently utilized in diabetes research (Chavez et al 2008). Previously we have shown that the adult baboon is a pertinent non-human primate model to examine the underlying cellular/molecular mechanisms responsible for insulin resistance, beta cell failure with islet of Langerhans remodeling and expansion of the glucagon cell component (Chavez et al 2008; Guardado et al 2009b; Guardado et al 2009a; Chavez et al 2009; Kamath et al 2011). Preterm baboons have significant gestational differences of key insulin signaling proteins in skeletal muscle, which may also contribute to neonatal hyperglycemia (Blanco et al 2010).…”

Section: Introductionmentioning

confidence: 99%

The ontogeny of the endocrine pancreas in the fetal/newborn baboon

Quinn¹,

Blanco²,

Perego³

et al. 2012

Journal of Endocrinology

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Background Erratic regulation of glucose metabolism including hyperglycemia is a common condition of premature infants and is associated with increased morbidity and mortality. Objective To examine histological and ultra-structural differences in the endocrine pancreas in fetal (throughout gestation) and neonatal baboons. Methods Twelve fetal baboons were delivered at 125 days (d) gestational age (GA), 140dGA, or 175dGA. Eight animals were delivered at term (185dGA); half were fed for 5d. Seventy-three non-diabetic adult baboons were used for comparison. Pancreatic tissue was studied utilizing light microscopy, confocal imaging and electron microscopy. Results The fetal and neonatal endocrine pancreas islet architecture became more organized as GA advanced. The percent areas of α-β-δ-cell type were similar within each fetal and newborn GA (NS), but were higher than the adults (P<0.05) regardless of GA. The ratio of β-cells within the islet (whole and core) increased with gestation (P<0.01). Neonatal baboons who survived for 5 days (feeding), had a 2.5-fold increase in pancreas weight compared to their counterparts euthanized at birth (P=0.01). Endocrine cells were found amongst exocrine ductal and acinar cells in 125,140 and 175dGA fetuses. Subpopulation of cells that co-expressed trypsin and glucagon/insulin show the presence of cells with mixed endo-exocrine lineage in fetuses. Conclusions The fetal endocrine pancreas has no prevalence of a of α-β-δ-cell type with larger endocrine cell percent areas than adults. Cells with mixed endocrine/exocrine phenotype occur during fetal development. Developmental differences may play a role in glucose homeostasis during the neonatal period and may have long term implications.

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Coordinated Defects in Hepatic Long Chain Fatty Acid Metabolism and Triglyceride Accumulation Contribute to Insulin Resistance in Non-Human Primates

Cited by 34 publications

References 61 publications

Selective cannabinoid-1 receptor blockade benefits fatty acid and triglyceride metabolism significantly in weight-stable nonhuman primates

Selective cannabinoid-1 receptor blockade benefits fatty acid and triglyceride metabolism significantly in weight-stable nonhuman primates

Ablating both Fabp1 and Scp2/Scpx (TKO) induces hepatic phospholipid and cholesterol accumulation in high fat-fed mice

The ontogeny of the endocrine pancreas in the fetal/newborn baboon

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