Protein Kinase Revealed to Regulate Body Weight and Energy Homeostasis

Researchers have identified a protein kinase that controls weight and homeostasis and when deficient or inactivated can lead to metabolic diseases like obesity and type 2 diabetes, according to a mouse study recently published in Endocrinology.

Researchers led by Eiichi Hinoi of the Laboratory of Pharmacology in the Department of Bioactive Molecules at Gifu Pharmaceutical University in Gifu, Japan, point out that an imbalance between energy intake and energy expenditure can lead to certain metabolic diseases like obesity and type 2 diabetes, which have become worldwide epidemics.

According to the authors, insulin helps to maintain body weight and energy metabolism through phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), the major pathways involved in insulin receptor (IR) signaling. “Moreover, leptin also modulates various cellular functions of hypothalamic leptin receptor (LepR)-expressing neurons and coordinates metabolic parameters, such as energy intake, energy expenditure, and glucose homeostasis, via the Janus tyrosine kinase signal transducer and activator of transcription (STAT), PI3K, and MAPK signaling pathways,” they write.

Extracellular signal-regulated kinase 5 (Erk5) is a member of the MAPK family and has been linked to odor discrimination and long-term memory, but little is known about how neuronal Erk5 affects body weight and homeostasis, so the researchers sought to reveal Erk5’s role in homeostasis through expression in the central nervous system (CNS). They used LepR-Cre mice, in which Cre recombinase is specifically expressed in LepR neurons involved in metabolisms that are abundantly localised in hypothalamus in the CNS. “Using specific Erk5-deficient mice with LepR-Cre, we [show] that Erk5 in LepR-expressing neurons contributes to body weight and systemic energy balance maintenance, and demonstrate a novel target for metabolic diseases such as obesity and type 2 diabetes,” the authors write.

“Erk5 deficiency in LepR-expressing neurons showed impaired glucose tolerance along with decreased physical activity, food intake, and energy expenditure.”

The researchers injected insulin into the mice, which induced phosphorylation of Erk5 in the hypothalamus. Moreover, Erk5 deficiency in leptin receptor (LepR)-expressing neurons led to an obesity phenotype, with an increased white adipose tissue mass due to increased adipocyte size only in female mice fed a normal chow diet. “Furthermore, Erk5 deficiency in LepR-expressing neurons showed impaired glucose tolerance along with decreased physical activity, food intake, and energy expenditure,” the authors write.

Based on their findings, the authors conclude that Erk5 controls body weight and energy homeostasis and could potentially be a novel target for metabolic diseases like obesity and type 2 diabetes. “Our findings may contribute to improving our understanding of the molecular mechanisms underlying the central control of body weight and energy homeostasis via hypothalamic neurons, and the manipulation of neuronal Mek5/Erk5 axis is a plausible strategy for coordinating a sophisticated balance between energy intake and energy expenditure required for protection against obesity and a variety of obesity-related metabolic diseases in humans,” the authors write.

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