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The neural precursor cell expressed developmentally down-regulated gene 4 (NEDD4) is a HECT-type E3 ubiquitin ligase that has received broad attention in recent years. Many of its reported substrates are active players in metabolism, implying a potential role of NEDD4 itself in metabolic regulation. Since homozygous Nedd4 deletion leads to embryonic or perinatal lethality, we investigated the function of NEDD4 in metabolic regulation in vivo, using Nedd4-haploinsufficient mice in a high fat dietinduced obesity (HFDIO) model. Our studies show that Nedd4-haploinsufficient mice fed a normal diet (ND) exhibited decreased body weight in both genders and proportionally reduced tissue mass compared to their age-matched wild-type littermates. The heterozygotic Nedd4-deficient mice displayed moderate insulin resistance and mild hyperinsulinemia. These findings are consistent with others’ studies in which depletion of Nedd4 in mouse embryonic fibroblasts (MEFs) led to a decline in insulin-like growth factor I (IGF-1) and insulin signaling. Surprisingly, Nedd4-haploinsufficient mice were partially protected against highfat diet (HFD) induced obesity. Total weight gain was decreased by 30% in Nedd4haploinsufficient mice on HFD, which was associated with reduced adiposity, improved insulin sensitivity in white adipose tissue (WAT), alleviated hepatic steatosis and attenuated lipid-induced inflammation. NEDD4 reduction did not affect serum glucose or lipid profile. The energy intake and physical activity were almost indistinguishable between the two groups. We present data indicating that these beneficial effects of Nedd4 haploinsufficiency under conditions promoting obesity or type 2 diabetes (T2D) derive from at least two mechanisms: 1) elevated levels of -agonist induced lipolysis through stimulation of -adrenergic signaling as evidenced by enhanced adrenergic receptor 2-AR) cell surface levels; 2) repressed expression of a key adipogenic regulator, peroxisome proliferator-activated receptor gamma (PPAR ) in Nedd4-haploinsufficient mice in the WAT. Downregulation of NEDD4 in 3T3-L1 preadipocytes impaired the adipogenic response, resulting in decreased PPAR expression. Thus, the reduced adiposity in Nedd4-haploinsufficient mice fed a HFD compared to littermate wild-type mice may be explained at least in part by their increased lipolysis and suppressed adipogenesis. Our data also imply that NEDD4 may have differential functions in modulating insulin signaling under physiological and pathological conditions. In this study, we tested the possible impact of NEDD4 reduction on cognitive function and anxiety behaviors. Preliminary results showed that Nedd4-haploinsufficient mice had impaired learning and memory performance but increased anxiety compared to wild-type littermates. NEDD4 may modulate different behavioral functions by targeting specific substrates for protein degradation in a brain-region-specific manner. Precise substrates that cause the alteration in such behaviors are yet to be determined by future studies.

Effect of Nedd4 Haploinsufficiency on Insulin Sensitivity, Adiposity and Neuronal Behaviors