Age is a major risk factor for the development of obesity and type 2 diabetes. However, how this process is regulated is poorly understood. Hypothalamic agouti-related peptide (AgRP) or the proopiomelanocortin (POMC), are important regulators of energy balance and glucose homeostasis. Notably, AgRP-deficient mice exhibit normal body weight as young adults but develop a lean phenotype as they age. We showed that AgRP neuronal innervation increases markedly with age onto specific neurons within the hypothalamus, and that this increased innervation exerts tonic inhibition onto these cells. Together these findings suggest that the age-associated increase in AgRP innervation is responsible for the increase in adiposity. However, the downstream components of this circuit are not well defined.

In a microarray screen, we identified ankyrin repeat and SOCS box-containing 4 (ASB4) as a potential downstream target of AgRP. We found that ASB4 protein is specifically expressed in brain areas innervated by AgRP. ASB4 expression in arcuate nucleus of the hypothalamus increases with age and ASB4 neurons are the prime targets of AgRP neuronal innervation that increases with age. As GWAS studies link ASB4 locus with human obesity we generated mice with germline deletion of ASB4. In direct contrast to the age-dependent leanness of AgRP-deficient mice, ASB4 knockout mice develop obesity with age. The loss of ASB4 also resulted in impaired glucose tolerance with age, independently of body adiposity. This weight-independent glucose intolerance phenotype was recapitulated when ASB4 was specifically removed from POMC neurons.

Together, we identified ASB4 as a key regulator of body weight and glucose homeostasis during aging. As ASB4 is known to be stimulated by leptin, our results suggest that the age-dependent increase of AgRP innervation onto ASB4 neurons may progressively inhibit ASB4 neuronal function with age, thereby attenuating the metabolic effects of anorexigenic hormones such as leptin whose levels increase with age.


E. Vagena: None. L. He: None. P. Engström: None. E. Yulyaningsih: None. D. Olson: Research Support; Self; MedImmune, Novo Nordisk A/S. A. Xu: None.


American Diabetes Association (1-18-PDF-023 to E.V.); Larry L. Hillblom Foundation

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at