Role of Hypothalamic Proopiomelanocortin Neuron Autophagy in the Control of Appetite and Leptin Response

Abstract

Autophagy is a catabolic cellular process involving the degradation of the cell's own components. Although the role of autophagy of diverse tissues in body metabolism has been investigated, the importance of autophagy in hypothalamic proopiomelanocortin (POMC) neurons, key regulators of energy balance, has not been addressed. The role of autophagy in leptin sensitivity that is critical for the control of body weight and appetite has also not been investigated. We produced mice with specific deletion of autophagy-related 7 (Atg7), an essential autophagy gene, in hypothalamic POMC neurons (Atg7(ΔPOMC) mice). Atg7 expression was deficient in the arcuate nucleus of the hypothalamus of Atg7(ΔPOMC) mice. p62, a specific substrate of autophagy, accumulated in the hypothalamus of Atg7(ΔPOMC) mice, which colocalized with ubiquitin. Atg7(ΔPOMC) mice had increased body weight due to increased food intake and decreased energy expenditure. Atg7(ΔPOMC) mice were not more prone to diet-induced obesity compared with control mice but more susceptible to hyperglycemia after high-fat diet. The ability of leptin to suppress fasting-elicited hyperphagia and weight gain during refeeding was attenuated in Atg7(ΔPOMC) mice. Deficient autophagy did not significantly affect POMC neuron number but impaired leptin-induced signal transducer and activation of transcription 3 activation. Our findings indicate a critical role for autophagy of POMC neurons in the control of energy homeostasis and leptin signaling.

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

“…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.…”

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

“…RNA from paraffin-embedded tissue blocks was prepared using a formalin-fixed paraffin-embedded kit (Qiagen, 56404). cDNA was synthesized using M-MLV reverse transcriptase (Promega, M17013) and oligo(dT) [12][13][14][15][16][17][18] primer. The expression of Atg7, Tnf, Il6, pro-Il1b, Adgre1, Tgfb, Ccl2, Ccl5, Cxcl1 and Actb was assessed by quantitative PCR using specific primer sets.…”

“…11,12 As these results suggest that autophagy deficiency is a proinflammatory condition particularly in relation to inflammasome activation, deficient autophagy can be a factor in the development of T2D associated with low-grade inflammation and inflammasome activation. Although the role of autophagy of diverse tissues in body metabolism has been intensively investigated, [13][14][15][16][17][18][19][20][21] the importance of autophagy of myeloid cells such as Mfs (macrophages) in the regulation of systemic insulin sensitivity and in the development of T2D has not been clearly elucidated. Besides metabolic syndrome, IBD (inflammatory bowel disease) is a prototypic disease associated with autophagy deficiency inducing aggravated tissue inflammation.…”