Loss of autophagy in hypothalamic POMC neurons impairs lipolysis

Abstract

Autophagy degrades cytoplasmic contents to achieve cellular homeostasis. We show that selective loss of autophagy in hypothalamic proopiomelanocortin (POMC) neurons decreases a-melanocyte-stimulating hormone (MSH) levels, promoting adiposity, impairing lipolysis and altering glucose homeostasis. Ageing reduces hypothalamic autophagy and a-MSH levels, and aged-mice phenocopy, the adiposity and lipolytic defect observed in POMC neuron autophagy-null mice. Intraperitoneal isoproterenol restores lipolysis in both models, demonstrating normal adipocyte catecholamine responsiveness. We propose that an unconventional, autophagosome-mediated form of secretion in POMC neurons controls energy balance by regulating a-MSH production. Modulating hypothalamic autophagy might have implications for preventing obesity and metabolic syndrome of ageing.

Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

“…This suggests that alterations in autophagic activity can modulate inter-organ crosstalk, a notion also supported by the observation of impaired lipolysis when autophagy was genetically disrupted in hypothalamic pro-opiomelanocortin (POMC) neurons [24].…”

“…Interestingly, hypothalamic inhibition of autophagy using ATG7 siRNA-mediated knockdown resulted in increased energy consumption and reduced energy expenditure, leading to impaired adipose lipolysis, exacerbation of obesity and whole-body insulin resistance in response to HFD feeding [24,52].…”

Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes

“…Autophagy knockout in adipose tissue also leads to protection from diet-induced obesity and insulin resistance together with impaired adipocyte differentiation 7,9 . Autophagy deficiency in hypothalamic proopiomelanocortin neurons leads to obesity and glucose intolerance [47][48][49] . In addition to the location of autophagy deficiency, severity of autophagy deficiency could also be important.…”

Autophagy at the crossroads of catabolism and anabolism

“…Autophagy has also been examined in another nutrient-sensing hypothalamic neuron, the proopiomelanocorti n (POMC) neuron, which produces anorexigenic neuropeptides that inhibit food intake and promote energy expenditure 87 . Multiple studies have demonstrated that Atg7 deletion in POMC neurons causes increased body weight owing to hyperphagia [87][88][89] .…”

“…Multiple studies have demonstrated that Atg7 deletion in POMC neurons causes increased body weight owing to hyperphagia [87][88][89] . However, more recent research argues against a general role for POMC neuron-specific autophagy in the control of energy homeostasis.…”