With close genomic and phenotypic similarity to humans, nonhuman primate models provide comprehensive epigenetic mimics of polycystic ovary syndrome (PCOS), suggesting early life targeting for prevention. Fetal exposure to testosterone (T), of all nonhuman primate emulations, provides the closest PCOS-like phenotypes, with early-to-mid gestation T-exposed female rhesus monkeys exhibiting adult reproductive, endocrinological and metabolic dysfunctional traits that are co-pathologies of PCOS. Late gestational T exposure, while inducing adult ovarian hyperandrogenism and menstrual abnormalities, has less dysfunctional metabolic accompaniment. Fetal exposures to dihydrotestosterone (DHT) or diethylstilbestrol (DES) suggest androgenic and estrogenic aspects of fetal programming. Neonatal exposure to T produces no PCOS-like outcome, while continuous T treatment of juvenile females causes precocious weight gain and early menarche (high T), or high LH and weight gain (moderate T). Acute T exposure of adult females generates polyfollicular ovaries, while chronic T exposure induces subtle menstrual irregularities without metabolic dysfunction.

Polycystic ovary syndrome (PCOS) is prevalent in reproductive-aged women and confounded by metabolic morbidities, including insulin resistance and type 2 diabetes. Although the etiology of PCOS is undefined, contribution of prenatal androgen (PA) exposure has been proposed in a rhesus monkey model as premenopausal PA female adults have PCOS-like phenotypes in addition to insulin resistance and decreased glucose tolerance. PA female infants exhibit relative hyperinsulinemia, suggesting prenatal sequelae of androgen excess on glucose metabolism and an antecedent to future metabolic disease. We assessed consequences of PA exposure on pancreatic islet morphology to identify evidence of programming on islet development. Islet counts and size were quantified and correlated with data from intravenous glucose tolerance tests (ivGTT) obtained from dams and their offspring. Average islet size was decreased in PA female infants along with corresponding increases in islet number, while islet fractional area was preserved. Infants also demonstrated an increase in both the proliferation marker Ki67 within islets and the beta to alpha cell ratio suggestive of enhanced beta cell expansion. PA adult females have reduced proportion of small islets without changes in proliferative or apoptotic markers, or in beta to alpha cell ratios. Together, these data suggest in utero androgen excess combined with mild maternal glucose intolerance alter infant and adult islet morphology, implicating deviant islet development. Marked infant, but subtle adult, morphological differences provide evidence of islet post-natal plasticity in adapting to changing physiologic demands: from insulin sensitivity and relative hypersecretion to insulin resistance and diminished insulin response to glucose in the mature PCOS-like phenotype.

Chronic high caloric intake has contributed to the increased prevalence of pediatric obesity and related morbidities. Most overweight or obese children, however, do not present with frank metabolic disease but rather insulin resistance or subclinical precursors. The innate immune system plays a role in the pathophysiology of type 2 diabetes but how it contributes to early metabolic dysfunction in children on chronic high-fat diet (HFD) is unclear. We hypothesize that such inflammation is present in the pancreas of children and is associated with early insulin resistance. We used nonhuman primate (NHP) juveniles exposed to chronic HFD as a model of early pediatric metabolic disease to demonstrate increased pancreatic inflammatory markers before the onset of significant obesity or glucose dysregulation. Pancreata from 13-month-old Japanese macaques exposed to a HFD from in utero to necropsy were analyzed for expression of cytokines and islet-associated macrophages. Parameters from an intravenous glucose tolerance test were correlated with cytokine expression. Before significant glucose dysregulation, the HFD cohort had a twofold increase in interleukin 6 (IL6), associated with decreased first-phase insulin response and a sexually dimorphic (male) increase in IL1b correlating with increased fasting glucose levels. The number of islet-associated macrophages was also increased. Pancreata from juvenile NHP exposed to HFD have increased inflammatory markers and evidence of innate immune infiltration before the onset of significant obesity or glucose dysregulation. Given the parallel development of metabolic disease between humans and NHPs, these findings have strong relevance to the early metabolic disease driven by a chronic HFD in children. Key Words" nonhuman primate " insulin resistance " increased islet-associated macrophages " high-fat diet

Our group recently demonstrated that maternal high-fat diet (HFD) consumption is associated with non-alcoholic fatty liver disease, increased apoptosis, and changes in gluconeogenic gene expression and chromatin structure in fetal nonhuman primate (NHP) liver. However, little is known about the long-term effects that a HFD has on hepatic nervous system development in offspring, a system that plays an important role in regulating hepatic metabolism. Utilizing immunohistochemistry and Real-Time PCR, we quantified sympathetic nerve fiber density, apoptosis, inflammation, and other autonomic components in the livers of fetal and one-year old Japanese macaques chronically exposed to a HFD. We found that HFD exposure in-utero and throughout the postnatal period (HFD/HFD), when compared to animals receiving a CTR diet for the same developmental period (CTR/CTR), is associated with a 1.7 fold decrease in periportal sympathetic innervation, a 5 fold decrease in parenchymal sympathetic innervation, and a 2.5 fold increase in hepatic apoptosis in the livers of one-year old male animals. Additionally, we observed an increase in hepatic inflammation and a decrease in a key component of the cholinergic anti-inflammatory pathway in one-year old HFD/HFD offspring. Taken together, these findings reinforce the impact that continuous exposure to a HFD has in the development of long-term hepatic pathologies in offspring and highlights a potential neuroanatomical basis for hepatic metabolic dysfunction.

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Sclerostin (SOST), a glycoprotein primarily derived from osteocytes, is an important regulator of bone remodeling. Osteogenesis imperfecta (OI) is a heritable disorder of bone characterized by low bone mass, bone fragility, recurrent fractures, and bone deformities. Altered SOST-mediated signaling may have a role in pathogenesis of type I collagen-related OI; however, this has not been evaluated in humans. We measured serum SOST levels in adults with OI who were enrolled in a randomized, placebo-controlled clinical trial that evaluated the effects of osteoanabolic therapy with teriparatide. Compared with age- and sex-matched control participants, mean SOST levels were lower in those with type I or types III/VI OI (p < 0.0001). Receiver operating curve analysis revealed that sclerostin alone or sclerostin plus bone mineral content discriminated patients with OI from controls (area under the curve 0.80 and 0.87, respectively). SOST levels increased in the group of patients with type I OI during therapy with teriparatide (compared with placebo, p = 0.01). The increase was significant at 6, 12, and 24 months of therapy (p ≤ 0.02) and was apparent as early as 3 months (p = 0.06). The magnitude of increases in SOST levels during therapy was inversely correlated with increases in vertebral volumetric bone mineral density (vBMD). Overall, these results suggest that: 1) SOST regulation is fundamentally altered in osteogenesis imperfecta; 2) serum SOST levels could be a biomarker of OI in adults; and 3) alterations in SOST may help predict the response to anabolic therapies in OI. © 2017 American Society for Bone and Mineral Research.

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