Defective Regulation of the Ubiquitin/Proteasome System in the Hypothalamus of Obese Male Mice

Abstract

In both human and experimental obesity, inflammatory damage to the hypothalamus plays an important role in the loss of the coordinated control of food intake and energy expenditure. Upon prolonged maintenance of increased body mass, the brain changes the defended set point of adiposity, and returning to normal weight becomes extremely difficult. Here we show that in prolonged but not in short-term obesity, the ubiquitin/proteasome system in the hypothalamus fails to maintain an adequate rate of protein recycling, leading to the accumulation of ubiquitinated proteins. This is accompanied by an increased colocalization of ubiquitin and p62 in the arcuate nucleus and reduced expression of autophagy markers in the hypothalamus. Genetic protection from obesity is accompanied by the normal regulation of the ubiquitin/proteasome system in the hypothalamus, whereas the inhibition of proteasome or p62 results in the acceleration of body mass gain in mice exposed for a short period to a high-fat diet. Thus, the defective regulation of the ubiquitin/proteasome system in the hypothalamus may be an important mechanism involved in the progression and autoperpetuation of obesity.

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

“…Several studies have explored the effects of long-term diet-induced obesity on hypothalamic function (13,14,15,16,17,44,46,47). Dysfunctions of different aspects of the protein homeostasis (proteostasis) machinery have emerged as important mechanisms contributing to hypothalamic neuronal damage.…”

“…A recent study has employed a real-time PCR array to evaluate the impact of dietary fat consumption on the expression of transcripts encoding hypothalamic proteins involved in the ubiquitin/proteasome system (UPS) (46). As a whole, the UPS is responsible for the degradation of up to 80% of short-lived proteins in any cell of the body (60).…”

“…Once ubiquitinated, proteins are sorted for degradation by the proteasome (61). In the hypothalamus of obese rodents, up to 15% of the proteins involved in the UPS are somehow modulated (46). This results in drastic changes in the amount of ubiquitinated proteins and proteasome in hypothalamic neurons (46).…”

“…In the hypothalamus of obese rodents, up to 15% of the proteins involved in the UPS are somehow modulated (46). This results in drastic changes in the amount of ubiquitinated proteins and proteasome in hypothalamic neurons (46). The longer the exposure to dietary fats, the more the UPS is affected, suggesting that the consumption of large amounts of dietary fats exerts a time-dependent effect that damages the UPS in key hypothalamic neurons, which impacts whole-body energy homeostasis (46).…”

“…Lean mice present constitutive autophagy in hypothalamic neurons (46,47). However, upon highfat feeding, the autophagic activity in the medium-basal hypothalamus is severely impaired (46,47,63).…”