Deficiency of p62/Sequestosome 1 Causes Hyperphagia Due to Leptin Resistance in the Brain

Abstract

The cytoplasmic regulatory protein p62 (Sequestosome 1/A170) is known to modulate various receptor-mediated intracellular signaling pathways. p62 deficiency was shown to result in mature-onset obesity in mice, but the mechanisms underlying this abnormality remained unclear. Here we report that hyperphagia due to central leptin resistance is the cause of obesity in p62 Ϫ/Ϫ mice. We found that these mice show hyperphagia. Restriction of food to the amount eaten by wild-type mice prevented excess body weight gain and fat accumulation, suggesting that overfeeding is the primary cause of obesity in p62 Ϫ/Ϫ mice. Brain-specific p62 deficiency caused mature-onset obesity to the same extent as in p62 Ϫ/Ϫ mice, further supporting a neuronal mechanism as the major cause of obesity in these mice. Immunohistochemical analysis revealed that p62 is highly expressed in hypothalamic neurons, including POMC neurons in the arcuate nucleus. Central leptin resistance was observed even in young preobese p62 Ϫ/Ϫ mice. We found a defect in intracellular distribution of the transcription factor Stat3, which is essential for the action of leptin, in p62 Ϫ/Ϫ mice. These results indicate that brain p62 plays an important role in bodyweight control by modulating the central leptin-signaling pathway and that lack of p62 in the brain causes leptin resistance, leading to hyperphagia. Thus, p62 could be a clinical target for treating obesity and metabolic syndrome.

Proteasome Dysfunction Activates Autophagy and the Keap1-Nrf2 Pathway

“…In this study, we developed genetically modified mice with decreased 26S proteasome activity, which accumulate aggregate structures positive for both ubiquitin and p62 in their cells, and found that proteasome-dysfunction activates selective autophagy and the Keap1-Nrf2 pathway, both of which serve as cellular defense mechanisms. , and the Nrf2-knock-out mice used in this study were described previously (33)(34)(35). Mice were housed in specific pathogen-free facilities, and the Ethics Review Committee for Animal Experimentation of the Tokyo Metropolitan Institute of Medical Science approved the experimental protocols.…”

Normal pancreatic β-cell function in mice with <i>RIP-Cre</i>-mediated inactivation of p62/SQSTM1

“…Further studies will hence be needed to determine the molecules that may compensate for p62 in p62 f/f :RIP-Cre mice. Harada et al reported that brain-specific p62 disruption by nestin-Cre results in significant body weight gain compared with control mice at 20 weeks of age [20]. Importantly, pair feeding completely abolished the obese phenotype of brain-specific p62 KO mice, indicating that p62 in the brain inhibits appetite and thus controls body weight homeostasis [20].…”

“…Harada et al reported that brain-specific p62 disruption by nestin-Cre results in significant body weight gain compared with control mice at 20 weeks of age [20]. Importantly, pair feeding completely abolished the obese phenotype of brain-specific p62 KO mice, indicating that p62 in the brain inhibits appetite and thus controls body weight homeostasis [20]. It has been demonstrated that RIP-Cre is expressed in a subset of neurons in the hypothalamus, and that deletion of Stat3 results in progressive obesity [30].…”

“…Rat insulin 2 promoter-driven Cre recombinase [23] was used to delete p62 in a pancreatic β-cell-specific manner. The generation of p62 flox/+ (f/+) mice was performed as described previously [20]. RIP-Cre mice were crossed with p62 …”

“…Mice with global inactivation of p62 (p62 -/-) were found to develop mature-onset obesity and several features of metabolic syndrome, including excess fat accumulation in white adipose tissue and liver, impaired glucose tolerance, and insulin sensitivity [19]. A subsequent study on brain-specific p62 knockout mice demonstrated that a lack of p62 in the brain causes leptin resistance, thereby leading to hyperphagia and obesity [20]. The p62 protein is also involved in several ageing-related pathologies.…”