Stress kinases in the modulation of metabolism and energy balance

Abstract

Obesity is a new global pandemic, with growing incidence and prevalence. This disease is associated with increased risk of several pathologies, including diabetes, cardiovascular diseases, and cancer. The mechanisms underlying obesity-associated metabolic changes are the focus of efforts to identify new therapies. Stress-activated protein kinases (SAPK), including cJun N-terminal kinases (JNKs) and p38, are required for cellular responses to metabolic stress and therefore might contribute to the pathogenesis of obesity. Tissue-specific knockout models support a cell-type-specific role for JNK isoforms, in particular JNK1, highlighting its importance in cell homeostasis and organ crosstalk. However, more efforts are needed to elucidate the specific roles of other JNK isoforms and p38 family members in metabolism and obesity. This review provides an overview of the role of SAPKs in the regulation of metabolism.

Keywords: JNK; SAPK; adipose tissue; brain and signal transduction; metabolism; obesity; p38; stress.

Figure 1. Stress-activated protein kinase signaling pathway.

Like all MAPK family members, the SAPKs, JNKs and p38s, are activated by a phosphorylation cascade. SAPKs are activated by stimuli such as cytokines and free fatty acids, which are abundant in the obese-state. Activation culminates with the phosphorylation of specific target proteins, inducing the appropriate cell response depending on the cell stimulus.

Figure 2. Organ-specific roles of JNK isoforms in metabolism.

JNK proteins play a pivotal role in metabolism. Functions of JNK1 and JNK2 are organ- and cell-specific, and have been extensively studied in tissue-specific knockout mouse models.

Figure 3. Roles of p38 isoforms in metabolism.

p38 targets include several proteins with a prominent role in metabolism regulation, such as TNF-alpha, C/EBPbeta, and PPARalpha, suggesting a role for these SAPKs in metabolism and metabolic disease. Further studies in tissue-specific knockout mouse models are needed to clarify the specific roles of each p38 isoform.