Loss of Autophagy in Pro-opiomelanocortin Neurons Perturbs Axon Growth and Causes Metabolic Dysregulation

Abstract

Summary The hypothalamic melanocortin system, which includes neurons that produce proopiomelanocortin (POMC)-derived peptides, is a major negative regulator of energy balance. POMC neurons begin to acquire their unique properties during neonatal life. The formation of functional neural systems requires massive cytoplasmic remodeling that may involve autophagy, an important intracellular mechanism for the degradation of damaged proteins and organelles. Here we investigated the functional and structural effects of the deletion of an essential autophagy gene, Atg7, in POMC neurons. Lack of Atg7 in POMC neurons caused higher post-weaning body weight, increased adiposity, and glucose intolerance. These metabolic impairments were associated with an age-dependant accumulation of ubiquitin/p62-positive aggregates in the hypothalamus and a disruption in the maturation of POMC-containing axonal projections. Together, these data provide direct genetic evidence that Atg7 in POMC neurons is required for normal metabolic regulation and neural development, and they implicate hypothalamic autophagy deficiency in the pathogenesis of obesity.

Autophagy at the crossroads of catabolism and anabolism

“…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.…”

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.…”

Weighing on autophagy

“…1). [7][8][9] These studies used a conditional cre-loxP approach to specifically delete Atg7 from POMC neurons. PomcCre; Atg7 loxploxp mice display higher body weights, hyperphagia and impaired glucose tolerance.…”

“…1). 7 PomcCre; Atg7 loxPloxP mice exhibit a reduced density of POMC-containing projections to each of their target nuclei, including the paraventricular nucleus of the hypothalamus, as early as postnatal day 14. These abnormalities in POMC neural projections persist throughout adult life and appear to be the result of diminished capacity of POMC neurons to extend axons.…”

“…PomcCre; Atg7 loxploxp mice display higher body weights, hyperphagia and impaired glucose tolerance. [7][8][9] These mice also exhibit an increased adiposity that is associated with leptin resistance. autophagy in POMC neurons develop an increased sensitivity to weight gain when they are fed a high-fat/high-energy diet.…”