Abstract
The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These effects of JNK3 deficiency were associated with enhanced excitatory signaling by AgRP neurons in HFD-fed mice. JNK3 therefore provides a mechanism that contributes to homeostatic regulation of energy balance in response to metabolic stress.
Highlights
The regulation of energy balance is important for health and survival
It is established that feeding a high fat diet (HFD) causes activation of the ubiquitously expressed isoforms JNK1 and JNK2 in peripheral tissues, including liver, muscle, and adipose tissue (Sabio and Davis, 2010)
We found that JNK3 deficiency in POMC neurons of HFD-fed mice caused no significant changes in feeding behavior, glucose intolerance, blood glucose concentration, hypertrophy of white and brown adipocytes, and hepatic steatosis compared with control Pomc-cre (PomcWT) mice (Figure 5A,C,E)
Summary
The regulation of energy balance (food consumption and energy expenditure) is important for health and survival. Sustained negative energy balance caused by cachexia and anorexia is associated with serious injury to multiple organ systems (Aoyagi et al, 2015; Mehler and Brown, 2015). Sustained positive energy balance caused by hyperphagia results in obesity associated with severe metabolic disorders (e.g. type 2 diabetes, cardiovascular disease, hepatitis, neurodegeneration and cancer) that represent leading causes of morbidity and mortality (Flegal et al, 2013). The homeostatic maintenance of energy balance is critically important. It is established that the arcuate nucleus (ARC) in the hypothalamus plays a key role in the regulation of energy balance (Cone, 2005). AgRP neurons in the ARC mediate orexigenic signals, including neuropeptide Y (NPY), agouti-related peptide (AgRP), and g-aminobutyric acid (GABA) that project
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
