The loss of skeletal muscle function with age, known as sarcopenia, significantly reduces independence and quality of life and can have significant metabolic consequences. Although exercise is effective in treating sarcopenia it is not always a viable option clinically, and currently, there are no pharmacological therapeutic interventions for sarcopenia. Here, we show that chronic treatment with pan-adiponectin receptor agonist AdipoRon improved muscle function in male mice by a mechanism linked to skeletal muscle metabolism and tissue remodeling. In aged mice, 6 weeks of AdipoRon treatment improved skeletal muscle functional measures in vivo and ex vivo. Improvements were linked to changes in fiber type, including an enrichment of oxidative fibers, and an increase in mitochondrial activity. In young mice, 6 weeks of AdipoRon treatment improved contractile force and activated the energy-sensing kinase AMPK and the mitochondrial regulator PGC-1a (peroxisome proliferator-activated receptor gamma coactivator one alpha). In cultured cells, the AdipoRon induced stimulation of AMPK and PGC-1a was associated with increased mitochondrial membrane potential, reorganization of mitochondrial architecture, increased respiration, and increased ATP production. Furthermore, the ability of AdipoRon to stimulate AMPK and PGC1a was conserved in nonhuman primate cultured cells. These data show that AdipoRon is an effective agent for the prevention of sarcopenia in mice and indicate that its effects translate to primates, suggesting it may also be a suitable therapeutic for sarcopenia in clinical application.

Aging is a multifactorial process characterized by progressive changes in gut physiology and the intestinal mucosal immune system. These changes, along with alterations in lifestyle, diet, nutrition, inflammation and immune function alter both composition and stability of the gut microbiota. Given the impact of environmental influences on the gut microbiota, animal models are particularly useful in this field. To understand the relationship between the gut microbiota and aging in nonhuman primates, we collected fecal samples from 20 male and 20 female rhesus macaques (Macaca mulatta), across the natural macaque age range, for 16S rRNA gene analyses. Operational taxonomic units were then grouped together to summarize taxon abundance at different hierarchical levels of classification and alpha- and beta-diversity were calculated. There were no age or sex differences in alpha diversity. At the phylum level, relative abundance of Proteobacteria and Firmicutes and Firmicutes to Bacteriodetes ratio were different between age groups though significance disappeared after correction for multiple comparisons. At the class level, relative abundance of Firmicutes_Bacilli decreased and Proteobacteria_Alphaproteobacteria and Proteobacteria_Betaproteobacteria increased with each successively older group. Only differences in Firmicutes_Bacilli remained significant after correction for multiple comparisons. No sex differences were identified in relative abundances after correction for multiple comparisons. Our results are not surprising given the known impact of environmental factors on the gut microbiota.

Background: Short-term (<1 year) calorie restriction (CR) has been reported to decrease physical activity and metabolic rate in humans and non-human primate models; however, studies examining the very long-term (>10 year) effect of CR on these parameters are lacking.Objective: The objective of this study was to examine metabolic and behavioral adaptations to long-term CR longitudinally in rhesus macaques.Design: Eighteen (10 male, 8 female) control (C) and 24 (14 male, 10 female) age matched CR rhesus monkeys between 19.6 and 31.9 years old were examined after 13 and 18 years of moderate adult-onset CR. Energy expenditure (EE) was examined by doubly labeled water (DLW; TEE) and respiratory chamber (24 h EE). Physical activity was assessed both by metabolic equivalent (MET) in a respiratory chamber and by an accelerometer. Metabolic cost of movements during 24 h was also calculated. Age and fat-free mass were included as covariates.Results: Adjusted total and 24 h EE were not different between C and CR. Sleeping metabolic rate was significantly lower, and physical activity level was higher in CR than in C independent from the CR-induced changes in body composition. The duration of physical activity above 1.6 METs was significantly higher in CR than in C, and CR had significantly higher accelerometer activity counts than C. Metabolic cost of movements during 24 h was significantly lower in CR than in C. The accelerometer activity counts were significantly decreased after seven years in C animals, but not in CR animals.Conclusions: The results suggest that long-term CR decreases basal metabolic rate, but maintains higher physical activity with lower metabolic cost of movements compared with C. (C) 2013 Elsevier Inc. All rights reserved.

Endometriosis affects a large percentage of the rhesus macaques (Macaca mulatta) at our institution. When the disease is diagnosed in macaques on long-term research protocols, the treatment of choice in our facility is monthly administration of medroxyprogesterone acetate (MPA) to decrease estrogen release and subsequently diminish clinical signs associated with the disease. Because hormonal fluctuations associated with the normal menstrual cycle are known to affect parameters of glucoregulatory function in rhesus macaques, we evaluated the effect of MPA treatment on glucoregulatory function cross-sectionally in 6 animals and longitudinally in 4 animals with endometriosis. Our hypothesis was that monthly administration of MPA for the treatment of endometriosis would negatively affect glucoregulatory function in rhesus macaques. We found that adult female rhesus macaques on MPA therapy for 1.4 to 36.1 mo had lower insulin sensitivity than did age- and weight-matched healthy control animals. In addition, glucoregulatory function was reduced after MPA treatment as compared with pretreatment levels in a group of 4 macaques. These data suggest that glucoregulatory function should be considered when endometriosis treatment is planned for rhesus macaques.

Calorie restriction (CR) is a dietary intervention shown to increase maximum life-span. The aim of this study was to compare the metabolizable energy of the pelleted semi-purified diet with estimated energy intake from food weight. Energy density of diet, urine and feces were measured by bomb calorimetry in rhesus monkeys (23–29 years old) on CR (CR, n=11) and control (C, n=9). Food moisture was measured to be 2-fold higher (9±1%) than indicated on the label (∼5%). The measured gross energy of diet was 4.4kcal/g dry weight of CR and 4.5kcal/g dry weight of C diets. In a two-day trial, food intake (mean±SD) was 112±20g and 136±26g of dry mass/d in the CR and C monkeys, respectively (p=0.003). The fraction of the diet absorbed (CR=0.91; C=0.95) was different (p<0.001) between CR and C monkeys. Using these coefficients, the metabolizable energy intake averaged over 6 months was 450±53 and 534±97kcal/d in CR and C monkeys, respectively (Diff=16%; p=0.03). These values were compared with energy expenditure (EE), as measured annually by indirect calorimetry (490±61kcal/d in CR and 532±62kcal/d in C monkeys). Adjusted for changes in body composition (2±10kcal/d in CR and −7±12kcal/d in C), energy balance was not different from zero in CR (−42±42kcal/d) and C (9±61kcal/d) monkeys. Use of diet weight is a reasonable estimate of the level of CR when food waste is assessed.

Introduction: Prenatally androgenized (PA) female rhesus monkeys share metabolic abnormalities in common with polycystic ovary syndrome (PCOS) women. Early gestation exposure (E) results in insulin resistance, impaired pancreatic β -cell function and type 2 diabetes, while late gestation exposure (L) results in supranormal insulin sensitivity that declines with increasing body mass index (BMI). Objective: To determine whether PA females have altered body fat distribution. Design: Five early-treated PA (EPA), five late-treated PA (LPA) and five control adult female monkeys underwent somatometrics, dual-X-ray absorptiometry (DXA) and abdominal computed tomography (CT). Five control and five EPA females underwent an intravenous glucose tolerance test to assess the relationship between body composition and glucoregulation. Results: There were no differences in age, weight, BMI or somatometrics. LPA females had ∼20% greater DXA-determined total fat and percent body fat, as well as total and percent abdominal fat than EPA or control females ( P ⩽0.05). LPA females also had ∼40% more CT-determined non-visceral abdominal fat than EPA or control females ( P ⩽0.05). The volume of visceral fat was similar among the three groups. EPA ( R 2 =0.94, P ⩽0.01) and LPA ( R 2 =0.53, P =0.16) females had a positive relationship between visceral fat and BMI, although not significant for LPA females. Conversely, control females had a positive relationship between non-visceral fat and BMI ( R 2 =0.98, P ⩽0.001). There was a positive relationship between basal insulin and total body ( R 2 =0.95, P ⩽0.007), total abdominal ( R 2 =0.81, P ⩽0.04) and visceral ( R 2 =0.82, P ⩽0.03) fat quantities in EPA, but not control females. Conclusions: Prenatal androgenization in female rhesus monkeys induces adiposity-dependent visceral fat accumulation, and late gestation androgenization causes increased total body and non-visceral fat mass. Early gestation androgenization induces visceral fat-dependent hyperinsulinemia. The relationship between the timing of prenatal androgen exposure and body composition phenotypes in this nonhuman primate model for PCOS may provide insight into the heterogeneity of metabolic defects found in PCOS women.

Caloric restriction (CR) is known to retard the aging process, and a marker of aging is decreased energy expenditure (EE). To assess longitudinal effects of CR on EE in rhesus monkeys (Macaca mulatta), data from 41 males (M) and 26 females (F) subjected to 9 or 15 yr of CR were studied. EE and body composition of monkeys 11-28 yr of age were measured using indirect calorimetry and dual X-ray absorptiometry. Total EE (24-h EE) was divided into daytime (day EE), nighttime (night EE), and daytime minus nighttime (D - N EE). M calorie-restricted monkeys showed a lower 24-h EE (means +/- SD = 568 +/- 96 kcal/day, P < 0.0001) than controls (C; 630 +/- 129 kcal/day). Calorie-restricted M had a lower night EE (difference = 36 kcal P < 0.0001) compared with C M, but after adjusting for FFM and FM, night EE was not different between calorie-restricted and C males (P = 0.72). The 24-h EE decreased with age (13 kcal decrease/yr, P < 0.0001), but there was no difference between CR and C. Adjusted for FFM and FM, D - N EE decreased with age (9 kcal/yr, P < 0.0001), with no interaction with age (P = 0.72). The F were compared with age-matched M selected from the male cohort. F had a lower 24-h EE (496 +/- 84 kcal/day) than M (636 +/- 139 kcal/day) (P < 0.0001). Adjusting for FFM and FM, night EE was lower in F compared with M (difference = 18 kcal, P = 0.077). Night EE did not differ between calorie-restricted and C younger monkeys after adjusting for FFM and FM. In conclusion, CR did not alter the age-related decrease in EE with CR.

Rhesus monkeys have been used as models to study obesity and disease. The aim of this study was to define body mass indices for underweight and obesity in rhesus monkeys. Longitudinal data collected over 8-14 years from 40 male and 26 female rhesus monkeys were analyzed. Body weight, insulin sensitivity index, and disposition index were regressed against percent body fat (%BF). A minimal %BF beyond which further loss of body weight resulted in loss of lean mass was determined to be 11.5% in older males, 8% in adult females, and 9% in younger adult males. Insulin sensitivity index and disposition index reached minimum values at 23% fat in older males, 18% in adult females, and 21% in younger adult males, indicating obesity. The estimated reference range for %BF was 9%-23% in male and 8%-18% in female monkeys, corresponding to body mass indices of 32-44 kg/m(2) for male and 27-35 kg/m(2) for female monkeys.

Polycystic ovary syndrome (PCOS) is a familial disease. Affected males harbor some of the metabolic deficits seen in affected females. The prenatally androgenized (PA) female rhesus monkey, an animal model for PCOS, manifests glucoregulatory and reproductive abnormalities similar to those seen in PCOS women. The purpose of this study was to determine whether exposure of fetal male rhesus monkeys to testosterone excess would induce glucoregulatory and reproductive deficits. Seven adult PA males and seven matched controls underwent somatometric measurements, sex steroid analysis, and a frequently sampled i.v. glucose tolerance test. Body measurements were similar in the two groups, although arm circumference was greater in control compared with PA males (P < 0.01). There were no differences in neonatal weight or serum levels of sex steroids between the two male groups. Measures of insulin sensitivity and pancreatic beta-cell compensation (disposition index) were clearly diminished in PA compared with control males [insulin sensitivity: PA, mean 0.8 (95% confidence interval, 0.11, 5.82); controls, 3.06 (1.51, 6.19) x 10(-4)/min/microU/ml; P < 0.05; disposition index: PA, 226.38 (69.54, 383.22); controls, 509.21/min (306.52, 711.89); P < 0.02]. PA males do not exhibit elevated androgens during adulthood, suggesting that insulin resistance and impaired pancreatic beta-cell function may result from fetal reprogramming of key metabolic tissues.

Intravenous glucose tolerance tests (IVGTT) were performed on 30 anesthetized, captive Sumatran (Pongo pygmaeus abeli), Bornean (P. p. pygmaeus), and hy brid (P. p. ablie x P. p. pygmaeus) orangutans, and fasted blood samples were taken from two additional juvenile orangutans in 11 U.S. toes from 1989 to 1997. The age range of animals was 3.5 to 40.5 years. Plasma and serum samples were assayed for glucose and insulin concentrations. Glucose disappearance rate (K-G), an index of glucose tolerance, was calculated, as were the early (acute) and second phase insulin responses to administered glucose. The mean +/- SE land median) fasting glucose and insulin concentrations were 113 +/- 16 mg/dL (90 mg/dL) and 45 +/- 7 mu U/mL (27 mu U/mL), respectively. Two animals previously suspected to be diabetic were easily identified by their markedly elevated fasting glucose concentrations (380 and 562 mg/dL) and relatively low fasted insulin concentrations (21 and 14 mu U/mL); their insulin responses during the IVGTTs were also low or non-detectable. Without these diabetics, the mean +/- SE (median) fasting glucose concentration was 92 +/- 18 mg/dL (89 mg/dL). Two animals, ages 18 and 40, were identified as potentially pre-diabetic based on age, adiposity, elevated fasted glucose (116 and 137 mg/dL, respectively), and elevated fasted insulin concentrations (114 and 217 mu U/mL, respectively). In addition, nearly half of the animals of varying ages, all sub-species and both sexes exhibited delayed or attenuated acute insulin responses during the IVGTTs, resulting in lower K-G (P < 0.04) and suggesting propensity for glucose intolerance in captive orangutans, Glucose and insulin concentrations and insulin responses to glucose did not differ between females on hormonal contraception regimes and those not receiving treatment. Zoo Biol 19:193-208, 2000. (C) 2000 Wiley-Liss, Inc.

Intravenous glucose tolerance tests (IVGTT) were performed on 30 anesthetized, captive Sumatran (Pongo pygmaeus abeli), Bornean (P. p. pygmaeus), and hybrid (P. p. ablie x P. p. pygmaeus) orangutans, and fasted blood samples were taken from two additional juvenile orangutans in 11 U.S. zoos from 1989 to 1997. The age range of animals was 3.5 to 40.5 years. Plasma and serum samples were assayed for glucose and insulin concentrations. Glucose disappearance rate (KG), an index of glucose tolerance, was calculated, as were the early (acute) and second phase insulin responses to administered glucose. The mean ± SE (and median) fasting glucose and insulin concentrations were 113 ± 16 mg/dL (90 mg/dL) and 45 ± 7 μU/mL (27 μU/mL), respectively. Two animals previously suspected to be diabetic were easily identified by their markedly elevated fasting glucose concentrations (380 and 562 mg/dL) and relatively low fasted insulin concentrations (21 and 14 μU/mL); their insulin responses during the IVGTTs were also low or non-detectable. Without these diabetics, the mean ± SE (median) fasting glucose concentration was 92 ± 18 mg/dL (89 mg/dL). Two animals, ages 18 and 40, were identified as potentially pre-diabetic based on age, adiposity, elevated fasted glucose (116 and 137 mg/dL, respectively), and elevated fasted insulin concentrations (114 and 217 μU/mL, respectively). In addition, nearly half of the animals of varying ages, all sub-species and both sexes exhibited delayed or attenuated acute insulin responses during the IVGTTs, resulting in lower KG (P < 0.04) and suggesting propensity for glucose intolerance in captive orangutans. Glucose and insulin concentrations and insulin responses to glucose did not differ between females on hormonal contraception regimes and those not receiving treatment. Zoo Biol 19:193–208, 2000. © 2000 Wiley-Liss, Inc.

Body size and composition were measured in forty-one adult Rhesus monkeys (Macaca mulatta) in order to characterize changes that occur during later life for both genders. Data were obtained by traditional somatometric techniques and by dual-energy X-ray absorptiometry. Representative monkeys were chosen within six categories defined by age (Young Adult, 6-9 year-old; Middle Aged, 15-19 year-old; Older Adult, 26-30 year-old), and sex. Body weight and most external measures of body size were greater during middle age and later life than in young adulthood, as were body fat content and lean body mass. Females tended to have a higher percentage body fat than males in all age categories. Lean tissue mass was markedly greater in the two younger groups for both sexes, compared to older adults. Bone mineral content and density were higher in the males than the females, but differences in bone mineralization among age groups did not achieve statistical significance. Such data derived from adult nonhuman primates are useful for defining fundamental biological changes with age in these species, and have value as a comparative model for studies of human aging and age-related morbidity.

The antidiabetic effects of pioglitazone hydrochloride were evaluated in 6 spontaneously obese, insulin-resistant rhesus monkeys. The animals were studied during six successive 2-wk treatment phases separated by 2-wk rest periods: two placebo phases; 0.3, 1.0, and 3.0 mg · kg−1 · day−1 pioglitazone hydrochloride phases; and a final placebo phase. During the second week of each treatment phase, serum insulin (immunoreactive insulin [IRI]), plasma glucose, and serum triglyceride (TG) levels were measured after an overnight fast and after a standardized meal. Blood pressure was measured and glucose tolerance tests (modified minimal model protocol) were performed a few days after the meal tests. Pioglitazone hydrochloride significantly improved fasting and postprandial levels of IRI, plasma glucose, and TG in a dose-related manner (P < 0.05). Fasting values during treatment with 3.0 mg · kg−1 · day−1 were reduced by 64% for IRI, 19% for plasma glucose, and 44% for TG compared with the placebo phase before treatment. Efficacy of pioglitazone hydrochloride was more marked for those animals with fasting hyperglycemia. Insulin sensitivity was increased by pioglitazone hydrochloride (P = 0.05), whereas glucose effectiveness and glucose disappearance rate were not detectably affected. Systolic and mean arterial blood pressures were significantly decreased by pioglitazone hydrochloride (P < 0.05). No toxic side effects of pioglitazone hydrochloride treatment were noted.