Differential adiponectin signalling couples ER stress with lipid metabolism to modulate ageing in C. elegans

Abstract

Abstract The metabolic and endocrine functions of adipose tissue and the ability of organisms to cope with cellular stress have a direct impact on physiological ageing and the aetiology of various diseases such as obesity-related pathologies and cancer. The endocrine effects of adipose tissue are mediated by secreted adipokines, which modulate metabolic processes and influence related maladies. Although a plethora of molecules and signaling pathways associate ageing with proteotoxic stress and cellular metabolism, our understanding of how these pathways interconnect to coordinate organismal physiology remains limited. We dissected the mechanisms linking adiponectin signalling pathways and endoplasmic reticulum (ER) proteotoxic stress responses that individually or synergistically affect longevity in C. elegans. Animals deficient for the adiponectin receptor PAQR-1 respond to ER stress, by rapidly activating the canonical ER unfolded protein response (UPRER) pathway, which is primed in these animals under physiological conditions by specific stress defence transcription factors. PAQR-1 loss enhances survival and promotes longevity under ER stress and reduced insulin/IGF-1 signalling. PAQR-1 engages UPRER, autophagy and lipase activity to modulate lipid metabolism during ageing. Our findings demonstrate that moderating adiponectin receptor -1 activity extends lifespan under stress, and directly implicate adiponectin signalling as a coupler between proteostasis and lipid metabolism during ageing.