Maternal obesity alters offspring liver and skeletal muscle metabolism in early post-puberty despite maintaining a normal post-weaning dietary lifestyle.

Maternal obesity (MO) during pregnancy is linked to increased and premature risk of age-related metabolic diseases in the offspring. However, the underlying molecular mechanisms still remain not fully understood. Using a well-established nonhuman primate model of MO, we analyzed tissue biopsies and plasma samples obtained from post-pubertal offspring (3-6.5 y) of MO mothers (n = 19) and from control animals born to mothers fed a standard diet (CON, n = 13). All offspring ate a healthy chow diet after weaning. Using untargeted gas chromatography-mass spectrometry metabolomics analysis, we quantified a total of 351 liver, 316 skeletal muscle, and 423 plasma metabolites. We identified 58 metabolites significantly altered in the liver and 46 in the skeletal muscle of MO offspring, with 8 metabolites shared between both tissues. Several metabolites were changed in opposite directions in males and females in both liver and skeletal muscle. Several tissue-specific and 4 shared metabolic pathways were identified from these dysregulated metabolites. Interestingly, none of the tissue-specific metabolic changes were reflected in plasma. Overall, our study describes characteristic metabolic perturbations in the liver and skeletal muscle in MO offspring, indicating that metabolic programming in utero persists postnatally, and revealing potential novel mechanisms that may contribute to age-related metabolic diseases later in life.

Walking speed declines with age in male and female baboons (Papio sp.): Confirmation of findings with sex as a biological variable.

We measured walking speed in baboons (67 female, 36 male; 5-22 years) to develop regression formulas to predict biological age. The final model strongly predicted age from just speed and sex. Walking speed is a valuable baboon aging biomarker. We present the first male speed data in a nonhuman primate.

Role of pregnancy and obesity on vitamin D status, transport, and metabolism in baboons.

Human studies show that obesity is associated with vitamin D insufficiency, which contributes to obesity-related disorders. Our aim was to elucidate the regulation of vitamin D during pregnancy and obesity in a nonhuman primate species. We studied lean and obese nonpregnant and pregnant baboons. Plasma 25-hydroxy vitamin D (25-OH-D) and 1α,25-(OH)2-D metabolites were analyzed using ELISA. Vitamin D-related gene expression was studied in maternal kidney, liver, subcutaneous fat, and placental tissue using real-time PCR and immunoblotting. Pregnancy was associated with an increase in plasma bioactive vitamin D levels compared with nonpregnant baboons in both lean and obese groups. Pregnant baboons had lower renal 24-hydroxylase CYP24A1 protein and chromatin-bound vitamin D receptor (VDR) than nonpregnant baboons. In contrast, pregnancy upregulated the expression of CYP24A1 and VDR in subcutaneous adipose tissue. Obesity decreased vitamin D status in pregnant baboons (162 ± 17 vs. 235 ± 28 nM for 25-OH-D, 671 ± 12 vs. 710 ± 10 pM for 1α,25-(OH)2-D; obese vs. lean pregnant baboons, P < 0.05). Lower vitamin D status correlated with decreased maternal renal expression of the vitamin D transporter cubulin and the 1α-hydroxylase CYP27B1. Maternal obesity also induced placental downregulation of the transporter megalin (LRP2), CYP27B1, the 25-hydroxylase CYP2J2, and VDR. We conclude that baboons represent a novel species to evaluate vitamin D regulation. Both pregnancy and obesity altered vitamin D status. Obesity-induced downregulation of vitamin D transport and bioactivation genes are novel mechanisms of obesity-induced vitamin D regulation.

Effect of maternal baboon (Papio sp.) dietary mismatch in pregnancy and lactation on post-natal offspring early life phenotype.

BACKGROUND: Non-human primate models of developmental programing by maternal mismatch between pregnancy and lactation diets are needed for translation to human programing outcomes. We present baboon offspring morphometry from birth to 3 years, and blood cortisol and adrenocorticotropin (ACTH) from 2 to 24 months. METHODS: Control mothers ate chow; mismatch mothers ate 30% less than controls during pregnancy and high-fat high-energy diet through lactation. RESULTS: Mismatch mothers lost weight during pregnancy. At birth, there were trends toward lower weight in mismatch offspring of both sexes (P = 0.06). From 0-3 years, catch-up growth occurred. Mismatch offspring male and female body weight increased faster than controls (P < 0.001). Mismatch female offspring showed greater increase in BMI (P < 0.001) and abdominal circumference (P = 0.008) vs controls. ACTH and cortisol slopes from 2 to 24 months of age were similar between groups in both sexes. Cortisol and ACTH increased after weaning in all groups. CONCLUSIONS: Mismatch produces sexually dimorphic post-natal growth phenotypes.

Effect of maternal obesity on fetal and postnatal baboon (Papio species) early life phenotype.

BACKGROUND: Non-human primate models of developmental programming by maternal obesity (MO) are needed for translation to human programming outcomes. We present baboon offspring (F1) morphometry, blood cortisol, and adrenocorticotropic hormone (ACTH) from 0.9 gestation to 0-2 years. METHODS: Control mothers ate chow; MO mothers ate high-fat high-energy diet pre-pregnancy through lactation. RESULTS: Maternal obesity mothers weighed more than controls pre-pregnancy. Maternal obesity gestational weight gain was lower with no correlation with fetal or placenta weights. At 0.9 gestation, MO and control F1 morphometry and ACTH were similar. MO-F1 0.9 gestation male cortisol was lower, rising slower from 0-2 years vs control-F1. At birth, male MO-F1 and control-F1 weights were similar, but growth from 0-2 years was steeper in MO-F1; newborn female MO-F1 weighed more than control-F1 but growth from 0-2 years was similar. ACTH did not change in either sex. CONCLUSIONS: Maternal obesity produced sexually dimorphic fetal and postnatal growth and hormonal phenotypes.

Ageing changes in biventricular cardiac function in male and female baboons (Papio spp.).

KEY POINTS: Life course changes in cardiovascular function in a non-human primate have been comprehensively characterized. Age-related declines in normalized left ventricular stroke volume and cardiac output were found with corresponding decreases in biventricular ejection fractions and filling rates. There were age-related decreases in male and female baboon normalized left ventricular myocardial mass index, which declined at similar rates. Systolic functional declines in right ventricular function were observed with age, similar to the left ventricle. Sex differences were found in the rates and directions of right ventricular volume changes along with decreased end-systolic right ventricular sphericity. The results validate the baboon as an appropriate model for translational studies of cardiovascular functional decline with ageing. ABSTRACT: Previous studies reported cardiac function declines with ageing. This study determined changes in biventricular cardiac function in a well-characterized baboon model. Cardiac magnetic resonance imaging measured key biventricular parameters in 47 baboons (22 female, age 4-23 years). ANCOVA assessed sex and age changes with P < 0.05 deemed significant. Stroke volume, cardiac output and other cardiac functional parameters were normalized to body surface area. There were similar, age-related rates of decrease in male (M) and female (F) normalized left ventricular (LV) myocardial mass index (M: -1.2 g m-2  year-1 , F: -0.9 g m-2  year-1 ). LV ejection fraction declined at -0.96% year-1 (r = -0.43, P = 0.002) and right ventricular (RV) ejection fraction decreased at -1.2% year-1 (r = -0.58, P < 0.001). Normalized LV stroke volume fell at -1.1 ml m-2  year-1 (r = -0.47, P = 0.001), normalized LV ejection rate at -3.8 ml s-1  m-2  year-1 (r = -0.43, P < 0.005) and normalized LV filling rate at -4.1 ml s-1  m-2  year-1 (r = -0.44, P < 0.005). Also, RV wall thickening fraction decreased with age (slope = -1% year-1 , P = 0.008). RV ejection rate decreased at -3.6 ml s-1  m-2  year-1 (P = 0.002) and the normalized average RV filling rate dropped at -3.7 ml s-1  m-2  year-1 (P < 0.0001). End-systolic RV sphericity index also dropped with age (r = -0.33, P = 0.02). Many observed changes parallel previously reported data in human and animal studies. These measured biventricular functional declines in hearts with ageing from the closest experimental primate species to man underscore the utility of the baboon model for investigating mechanisms related to heart ageing.

Intrauterine growth restriction results in persistent vascular mismatch in adulthood.

KEY POINTS: Intrauterine growth restriction (IUGR) increases offspring risk of chronic diseases later in life, including cardiovascular dysfunction. Our prior studies suggest biventricular cardiac dysfunction and vascular impairment in baboons who were IUGR at birth because of moderate maternal nutrient reduction. The current study reveals changes in artery sizes, distensibility, and blood flow pattern in young adult IUGR baboons, which may contribute to cardiac stress. The pattern of abnormality observed suggests that vascular redistribution seen with IUGR in fetal life may continue into adulthood. ABSTRACT: Maternal nutrient reduction induces intrauterine growth restriction (IUGR), increasing risks of chronic diseases later in life, including cardiovascular dysfunction. Using ultrasound, we determined regional blood flow, blood vessel sizes, and distensibility in IUGR baboons (8 males, 8 females, 8.8 years, similar to 35 human years) and controls (12 males, 12 females, 9.5 years). The measured blood vessels were larger in size in the males compared to females before but not after normalization to body surface area. Smaller IUGR normalized blood vessel sizes were observed in the femoral and external iliac arteries but not the brachial or common carotid arteries and not correlated significantly with birth weight. Mild decrease in distensibility in the IUGR group was seen in the iliac but not the carotid arteries without between-sex differences. In IUGR baboons there was increased carotid arterial blood flow velocity during late systole and diastole. Overall, our findings support the conclusion that region specific vascular and haemodynamic changes occur with IUGR, which may contribute to the occurrence of later life cardiac dysfunction. The pattern of alteration observed suggests vascular redistribution efforts in response to challenges in the perinatal period may persist into adulthood. Further studies are needed to determine the life course progression of these changes.

Sex-dimorphic acceleration of pericardial, subcutaneous, and plasma lipid increase in offspring of poorly nourished baboons.

Developmental programming by reduced maternal nutrition alters function in multiple offspring physiological systems, including lipid metabolism. We have shown that intrauterine growth restriction (IUGR) leads to offspring cardiovascular dysfunction with an accelerated aging phenotype in our nonhuman primate, baboon model. We hypothesized age-advanced pericardial fat and blood lipid changes. In pregnancy and lactation, pregnant baboons ate ad lib (control) or 70% ad lib diet (IUGR). We studied baboon offspring pericardial lipid deposition with magnetic resonance imaging at 5-6 years (human equivalent 20-24 years), skinfold thickness, and serum lipid profile at 8-9 years (human equivalent 32-36 years), comparing values with a normative life-course baboon cohort, 4-23 years. Increased pericardial fat deposition occurred in IUGR males but not females. Female but not male total cholesterol, low-density lipoprotein, and subcutaneous fat were increased with a trend of triglycerides increase. When comparing IUGR changes to values in normal older baboons, the increase in male apical pericardial fat was equivalent to advancing age by 6 years and the increase in female low-density lipoprotein to an increase of 3 years. We conclude that reduced maternal diet accelerates offspring lipid changes in a sex-dimorphic manner. The interaction between programming and accelerated lipogenesis warrants further investigation.

Efficacy and safety of antenatal steroids.

Antenatal steroids (ANS) are among the most important and widely utilized interventions to improve outcomes for preterm infants. A significant body of evidence demonstrates improved outcomes in preterm infants (24-34 wk) delivered between 1 and 7 days after the administration of a single course of ANS. Moreover, ANS have the advantage of being widely available, low cost, and easily administered via maternal intramuscular injection. The use of ANS to mature the fetal lung is, however, not without contention. Their use in pregnancy is not FDA approved, and treatment doses and regimens remain largely unoptimized. Their mode of use varies considerably between countries, and there are lingering concerns regarding the safety of exposing the fetus to high doses of exogenous steroids. A significant proportion of women deliver outside the 1- to 7-day therapeutic window after ANS treatment, and this delay may be associated with an increased risk of adverse outcomes for both mother and baby. Today, animal-based studies are one means by which key questions of dosing and safety relating to ANS may be resolved, allowing for further refinement(s) of this important therapy. Complementary approaches using nonhuman primates, sheep, and rodents have provided invaluable advances to our understanding of how exogenous steroid exposure impacts fetal development. Focusing on these three major model groups, this review highlights the role of three key animal models (sheep, nonhuman primates, rodents) in the development of antenatal steroid therapy, and provides an up-to-date synthesis of current efforts to refine this therapy in an era of personalised medicine.

2D:4D digit ratio is not a biomarker of developmental programming in baboons (Papio hamadryas species).

We hypothesized second-to-fourth hand digit ratio (2D:4D) is a biomarker of developmental programming in 3 baboon groups: intrauterine growth restriction (7 females, 8 males), exposure during fetal life to synthetic glucocorticoids (4 females, 5 males), and controls (66 females, 20 males). 2D:4D was similar between sexes and groups.

Reproductive cycling in adult baboons (Papio species) that were intrauterine growth restricted at birth implies normal fertility but increased psychosocial stress.

We investigated menstrual cycles in intrauterine growth restricted (IUGR, 7-10 years, n = 8) and age-matched control (n = 10) baboons. Cycle duration and plasma anti-Mullerian hormone were similar. IUGR spent more days per cycle swollen and had elevated early morning fasted serum cortisol, suggesting normal fertility in the presence of increased psychosocial stress.

Maternal activity, anxiety, and protectiveness during moderate nutrient restriction in captive baboons (Papio sp.).

BACKGROUND: We hypothesized that maternal nutrient restriction (NR) would increase activity and behavioral indicators of anxiety (self-directed behaviors, SDBs) in captive baboons (Papio sp.) and result in more protective maternal styles. METHODS: Our study included 19 adult female baboons. Seven females ate ad libitum (control group), and eight females ate 30% less (NR group) and were observed through pregnancy and lactation. RESULTS: Control females engage in higher rates of SDB than NR females overall (P ≤ .018) and during the prenatal period (P ≤ .001) and engage in more aggressive behavior (P ≤ .033). Control females retrieved infants more than NR females during weeks 5-8 postpartum (P ≤ .019). CONCLUSIONS: Lower SDB rates among prenatal NR females reduce energy expenditure and increase available resources for fetal development when nutritionally restricted. Higher infant retrieval rates by controls may indicate more infant independence rather than maternal style differences.

Maternal nutrient restriction during pregnancy and lactation leads to impaired right ventricular function in young adult baboons.

KEY POINTS: Maternal nutrient restriction induces intrauterine growth restriction (IUGR) and leads to heightened cardiovascular risks later in life. We report right ventricular (RV) filling and ejection abnormalities in IUGR young adult baboons using cardiac magnetic resonance imaging. Both functional and morphological indicators of poor RV function were seen, many of which were similar to effects of ageing, but also with a few key differences. We observed more pronounced RV changes compared to our previous report of the left ventricle, suggesting there is likely to be a component of isolated RV abnormality in addition to expected haemodynamic sequelae from left ventricular dysfunction. In particular, our findings raise the suspicion of pulmonary hypertension after IUGR. This study establishes that IUGR also leads to impairment of the right ventricle in addition to the left ventricle classically studied. ABSTRACT: Maternal nutrient restriction induces intrauterine growth restriction (IUGR), increasing later life chronic disease including cardiovascular dysfunction. Our left ventricular (LV) CMRI studies in IUGR baboons (8 M, 8 F, 5.7 years - human equivalent approximately 25 years), control offspring (8 M, 8 F, 5.6 years), and normal elderly (OLD) baboons (6 M, 6 F, mean 15.9 years) revealed long-term LV abnormalities in IUGR offspring. Although it is known that right ventricular (RV) function is dependent on LV health, the IUGR right ventricle remains poorly studied. We examined the right ventricle with cardiac magnetic resonance imaging in the same cohorts. We observed decreased ejection fraction (49 ± 2 vs. 33 ± 3%, P < 0.001), cardiac index (2.73 ± 0.27 vs. 1.89 ± 0.20 l min-1 m-2 , P < 0.05), early filling rate/body surface area (BSA) (109.2 ± 7.8 vs. 44.6 ± 7.3 ml s-1  m-2 , P < 0.001), wall thickening (61 ± 3 vs. 44 ± 5%, P < 0.05), and longitudinal shortening (26 ± 3 vs. 15 ± 2%, P < 0.01) in IUGR animals with increased chamber volumes. Many, but not all, of these changes share similarities to normal older animals. Our findings suggest IUGR-induced pulmonary hypertension should be further investigated and that atrial volume, pulmonic outflow and interventricular septal motion may provide valuable insights into IUGR cardiovascular physiology. Overall, our findings reaffirm that gestational and neonatal challenges can result in long-term programming of poor offspring cardiovascular health. To our knowledge, this is the first study reporting IUGR-induced programmed adult RV dysfunction in an experimental primate model.

Cardiac remodelling in a baboon model of intrauterine growth restriction mimics accelerated ageing.

KEY POINTS: Rodent models of intrauterine growth restriction (IUGR) successfully identify mechanisms that can lead to short-term and long-term detrimental cardiomyopathies but differences between rodent and human cardiac physiology and placental-fetal development indicate a need for models in precocial species for translation to human development. We developed a baboon model for IUGR studies using a moderate 30% global calorie restriction of pregnant mothers and used cardiac magnetic resonance imaging to evaluate offspring heart function in early adulthood. Impaired diastolic and systolic cardiac function was observed in IUGR offspring with differences between male and female subjects, compared to their respective controls. Aspects of cardiac impairment found in the IUGR offspring were similar to those found in normal controls in a geriatric cohort. Understanding early cardiac biomarkers of IUGR using non-invasive imaging in this susceptible population, especially taking into account sexual dimorphisms, will aid recognition of the clinical presentation, development of biomarkers suitable for use in humans and management of treatment strategies. ABSTRACT: Extensive rodent studies have shown that reduced perinatal nutrition programmes chronic cardiovascular disease. To enable translation to humans, we developed baboon offspring cohorts from mothers fed ad libitum (control) or 70% of the control ad libitum diet in pregnancy and lactation, which were growth restricted at birth. We hypothesized that intrauterine growth restriction (IUGR) offspring hearts would show impaired function and a premature ageing phenotype. We studied IUGR baboons (8 male, 8 female, 5.7 years), control offspring (8 male, 8 female, 5.6 years - human equivalent approximately 25 years), and normal elderly (OLD) baboons (6 male, 6 female, mean 15.9 years). Left ventricular (LV) morphology and systolic and diastolic function were evaluated with cardiac MRI and normalized to body surface area. Two-way ANOVA by group and sex (with P < 0.05) indicated ejection fraction, 3D sphericity indices, cardiac index, normalized systolic volume, normalized LV wall thickness, and average filling rate differed by group. Group and sex differences were found for normalized LV wall thickening and normalized myocardial mass, without interactions. Normalized peak LV filling rate and diastolic sphericity index were not correlated in control but strongly correlated in OLD and IUGR baboons. IUGR programming in baboons produces myocardial remodelling, reduces systolic and diastolic function, and results in the emergence of a premature ageing phenotype in the heart. To our knowledge, this is the first demonstration of the specific characteristics of cardiac programming and early life functional decline with ageing in an IUGR non-human primate model. Further studies across the life span will determine progression of cardiac dysfunction.

Effect of moderate, 30 percent global maternal nutrient reduction on fetal and postnatal baboon phenotype.

BACKGROUND: Most developmental programming studies on maternal nutrient reduction (MNR) are in altricial rodents whose maternal nutritional burden and offspring developmental trajectory differ from precocial non-human primates and humans. METHODS: Control (CTR) baboon mothers ate ad libitum; MNR mothers ate 70% global control diet in pregnancy and lactation. RESULTS: We present offspring morphometry, blood cortisol, and adrenocorticotropin (ACTH) during second half of gestation (G) and first three postnatal years. Moderate MNR produced intrauterine growth restriction (IUGR). IUGR males (n=43) and females (n=28) were smaller than CTR males (n=50) and females (n=47) in many measurements at many ages. In CTR, fetal ACTH increased 228% and cortisol 48% between 0.65G and 0.9G. IUGR ACTH was elevated at 0.65G and cortisol at 0.9G. 0.9G maternal gestational weight gain, fetal weight, and placenta weight were correlated. CONCLUSIONS: Moderate IUGR decreased body weight and morphometric measurements at key time points and altered hypothalamo-pituitary-adrenal function.

Walking speed as an aging biomarker in baboons (Papio hamadryas).

BACKGROUND: Walking speed is an important human aging biomarker. Baboons are valuable translational models for aging studies. Establishing whether walking speed is a good aging biomarker has value. We hypothesized there would be characteristic age-related decline in baboon walking speed. METHODS: We studied 33 female baboons aged 5-21 years. Walking speed was calculated by the time to walk between landmarks separated by known distances. A regression model was developed to describe the relationship between speed, age, and body weight. RESULTS: Speed negatively associated with age, a relationship enhanced by increased weight (P < 0.0005). For 16-kg animals, speed declined approximately 0.6 cm/s yearly. For each additional kilogram of weight, speed declined an additional 0.3 cm/s yearly. CONCLUSIONS: Baboon walking speed declines with age, an effect modulated by weight. Ease of measurement and strong age association make walking speed a valuable biomarker for aging research with this important experimental species.

Increased aggressive and affiliative display behavior in intrauterine growth restricted baboons.

BACKGROUND: We hypothesized intrauterine growth restricted offspring (IUGR) demonstrate higher rates of aggression and higher dominance ranks than control (CTR) offspring with normal weight at term; if aggressive behavior is advantageous during resource scarcity, developmental programming may lead to an association between aggression and IUGR. METHODS: We studied 22 group-housed baboons (ages 3-5 years). CTR (male n = 8, female n = 5) mothers ate ad libitum. IUGR (male n = 4, female n = 5) mothers were fed 70% feed eaten by CTR mothers during pregnancy and lactation. RESULTS: IUGR showed higher rates of aggressive displays (P < 0.01) and friendly displays (P < 0.02). Dominance ranks and physical aggression rates did not differ between groups. CONCLUSIONS: High rates of IUGR aggressive display might reflect developmental programming of behavioral phenotypes enhancing fitness. Friendly displays may reflect reconciliation. Potential mechanisms include neurodevelopment and learning. Exploration of IUGR as a risk factor for behavioral patterns is important for developing diagnostic and therapeutic strategies.

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons.

Biological resilience, broadly defined as the ability to recover from an acute challenge and return to homeostasis, is of growing importance to the biology of aging. At the cellular level, there is variability across tissue types in resilience and these differences are likely to contribute to tissue aging rate disparities. However, there are challenges in addressing these cell-type differences at regional, tissue, and subject level. To address this question, we established primary cells from aged male and female baboons between 13.3 and 17.8 years spanning across different tissues, tissue regions, and cell types including (1) fibroblasts from skin and from the heart separated into the left ventricle (LV), right ventricle (RV), left atrium (LA), and right atrium (RA); (2) astrocytes from the prefrontal cortex and hippocampus; and (3) hepatocytes. Primary cells were characterized by their cell surface markers and their cellular respiration was assessed with Seahorse XFe96. Cellular resilience was assessed by modifying a live-cell imaging approach; we previously reported that monitors proliferation of dividing cells following response and recovery to oxidative (50 µM-H2O2), metabolic (1 mM-glucose), and proteostasis (0.1 µM-thapsigargin) stress. We noted significant differences even among similar cell types that are dependent on tissue source and the diversity in cellular response is stressor-specific. For example, astrocytes had a higher oxygen consumption rate and exhibited greater resilience to oxidative stress (OS) than both fibroblasts and hepatocytes. RV and RA fibroblasts were less resilient to OS compared with LV and LA, respectively. Skin fibroblasts were less impacted by proteostasis stress compared to astrocytes and cardiac fibroblasts. Future studies will test the functional relationship of these outcomes to the age and developmental status of donors as potential predictive markers.

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons.

Biological resilience, broadly defined as ability to recover from acute challenge and return to homeostasis, is of growing importance to the biology of aging. At the cellular level, there is variability across tissue types in resilience and these differences likely to contribute to tissue aging rate disparities. However, there are challenges in addressing these cell-type differences at regional, tissue and subject level. To address this question, we established primary cells from aged male and female baboons between 13.3-17.8 years spanning across different tissues, tissue regions, and cell types including: (1) fibroblasts from skin and from heart separated into left ventricle (LV), right ventricle (RV), left atrium (LA) and right atrium (RA), (2) astrocytes from the prefrontal cortex and hippocampus and (3) hepatocytes. Primary cells were characterized by their cell surface markers and their cellular respiration assessed with Seahorse XFe96. Cellular resilience was assessed by modifying a live-cell imaging approach we previously reported that monitors proliferation of dividing cells following response and recovery to oxidative (50µM-H2O2), metabolic (1mM-glucose) and proteostasis (0.1µM-thapsigargin) stress. We noted significant differences even among similar cell types that are dependent on tissue source and the diversity in cellular response is stressor specific. For example, astrocytes were more energetic and exhibited greater resilience to oxidative stress (OS) than both fibroblasts and hepatocytes. RV and RA fibroblasts were less resilient to OS compared with LV and LA respectively. Skin fibroblasts were less impacted by proteostasis stress compared to astrocytes and cardiac fibroblasts. Future studies will test the functional relationship of these outcomes to age and developmental status of donors as potential predictive markers.

Perinatal maternal undernutrition in baboons modulates hepatic mitochondrial function but not metabolites in aging offspring.

We previously demonstrated in baboons that maternal undernutrition (MUN), achieved by 70 % of control nutrition, impairs fetal liver function, but long-term changes associated with aging in this model remain unexplored. Here, we assessed clinical phenotypes of liver function, mitochondrial bioenergetics, and protein abundance in adult male and female baboons exposed to MUN during pregnancy and lactation and their control counterparts. Plasma liver enzymes were assessed enzymatically. Liver glycogen, choline, and lipid concentrations were quantified by magnetic resonance spectroscopy. Mitochondrial respiration in primary hepatocytes under standard culture conditions and in response to metabolic (1 mM glucose) and oxidative (100 µM H2O2) stress were assessed with Seahorse XFe96. Hepatocyte mitochondrial membrane potential (MMP) and protein abundance were determined by tetramethylrhodamine ethyl ester staining and immunoblotting, respectively. Liver enzymes and metabolite concentrations were largely unaffected by MUN, except for higher aspartate aminotransferase levels in MUN offspring when male and female data were combined. Oxygen consumption rate, extracellular acidification rate, and MMP were significantly higher in male MUN offspring relative to control animals under standard culture. However, in females, cellular respiration was similar in control and MUN offspring. In response to low glucose challenge, only control male hepatocytes were resistant to low glucose-stimulated increase in basal and ATP-linked respiration. H2O2 did not affect hepatocyte mitochondrial respiration. Protein markers of mitochondrial respiratory chain subunits, biogenesis, dynamics, and antioxidant enzymes were unchanged. Male-specific increases in mitochondrial bioenergetics in MUN offspring may be associated with increased energy demand in these animals. The similarity in systemic liver parameters suggests that changes in hepatocyte bioenergetics capacity precede detectable circulatory hepatic defects in MUN offspring and that the mitochondria may be an orchestrator of liver programming outcome.