Early Metabolic Syndrome (MetS) in Chronic Rhesus Macaque Model of Human Allergic Asthma

Abstract

Human asthma, obesity, MetS, overt Type 2 diabetes, and related sequelae such as cardiovascular diseases, account for much of the mortality and morbidity worldwide. The etiology and complex physiological mechanisms underlying these pathological states intersect within the human body – and within Rhesus macaques. Much like humans, these animals (in captivity) often develop spontaneous, age‐related obesity. Hence, these animals are ideally suited for investigations of obesity and metabolism, as well as chronic allergic asthma.In 2013, twenty animals were sensitized by i.p. injection of house dust mite antigen (HDM) adsorbed to alum; airway sensitization and maintenance were accomplished by exposure to aerosolized HDM (aeroHDM) at ≥ 2‐week intervals, to a dose that induced an acute asthmatic response: ≥ 100% increase in lung resistance, ≥ 40% decrease in dynamic compliance, and/or peripheral oxygen saturation ≤ 70%. Periodically, we assessed the late phase asthmatic response 24 hours after aeroHDM exposure: airway hyperreactivity was assessed by aerosolized methacholine challenge; pulmonary inflammation was assessed by bronchoalveolar lavage. Occasionally animals were also exposed to an experimental asthma therapeutic.In 2018, ten animals had developed obesity and were suspected to harbor other clinical manifestations of MetS. Retrospective analyses confirmed relative hypertension in animals that had robust responsiveness to aeroHDM and were > 16 kg. Using archived frozen serum samples, we reconstructed the biochemical history of adiposity development and glucose metabolism ‐ a story that was evolving coincident with chronic exposures to both Diet A and aeroHDM (Fig. 1). By age 10 years, 4/5 of the largest animals (body weight, 21 ± 2 kg; waist circumference in lateral recumbency, 68 ± 5 cm; BMI using crown‐to‐rump length, 53 ± 3 kg/m2: values are mean ± SD) had insulin resistance (peak HOMA‐IR, 61 ± 29) associated with leptin > 14 ng/ml and total adiponectin < 3.5 μg/ml; 3/5 animals had dyslipidemia (Fig. 2); 1/5 animals had diabetes by age 8 years – 4 to 6 years earlier than would be expected based on non‐human primate literature. Biomarkers of inflammation and oxidative stress are outstanding.In July 2019, six months after switching to lower carbohydrate/higher protein Diet B, and > 12 months since the last aeroHDM exposure: all animals lost weight coincident with larger animals resolving insulin resistance, dyslipidemia, and diabetes. As seen in some obese asthmatic humans, larger animals had higher pulmonary inflammation (especially neutrophilic) and higher airway hyperreactivity to aerosolized methacholine.We concluded that chronic allergic inflammation synergized with inflammation of developing adiposity, accelerating onset of MetS in susceptible animals. We hypothesize that resumption of chronic periodic aeroHDM exposure will trigger more rapid progression/re‐establishment of MetS, IR, and eventually overt Type 2 diabetes if we do not intervene.Historical event timeline.Figure 1Body weight and serum triglycerides of 5 largest animals (mean ± SD: n=3 to 5 for each time point). Gray vertical bar: gradual transition to lower carbohydrate/higher protein Diet B.Figure 2