What is leptin's relationship to PEPCK? Does it stimulate or suppress it? Would love to hear thoughts on this from the sciencey types on here.
edit: I think it's probably got to increase PEPCK... the second study measured a short term leptin exposure, as opposed to longer term leptin sensitivity.
Leptin upregulates PEPCK expression
shows that the rats receiving leptin for 6 h manifested a ~3-fold increase in PEPCK mRNA concentrations compared with vehicle-infused rats. Most importantly, this marked stimulation of PEPCK gene expression by leptin was observed in the presence of equal and physiologically elevated plasma insulin concentrations. Thus, leptin appeared to antagonize the effect of insulin on PEPCK gene expression in vivo.
In conclusion, leptin both alone and in combination with insulin reduces hepatic glucose production by decreasing the synthesis of the key enzyme of gluconeogenesis, PEPCK, which results mainly from the stimulation of the IRS-2 pathway.
In summary, a short-term exposure to leptin 1) reduces hepatic gluconeogenesis by reducing PEPCK activity; 2) interferes with insulin signaling, exerting both an insulin-like and -antagonistic effect in liver tissue;
ICV leptin resulted in a 2???3-fold increase in hepatic phosphoenolpyruvate carboxykinase mRNA levels.
asked byJeff__1 (15236)
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on July 03, 2012
at 09:12 PM
The Quilt is so far ahead of his time it's not funny. His year old posts are just starting to make sense.
Now, researchers at Beth Israel Deaconess Medical Center (BIDMC) have identified the mechanism responsible for inhibition of AMPK activity in the hypothalamus, a discovery that not only provides a deeper understanding of energy balance but also reveals a critical integration point where multiple signaling pathways, including PI3K-AKT and mTOR converge.
Described in the July 3 issue of Cell Metabolism, the findings could yield new opportunities for the development of treatments for both metabolic diseases and cancer.
"AMPK is an evolutionarily conserved 'fuel gauge,'" says senior author Barbara Kahn, MD, a scientist in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and the George Richards Minot Professor of Medicine at Harvard Medical School. Activated when cellular energy supplies are low, AMPK also functions at the whole body level to regulate metabolism and energy balance.
The Kahn laboratory was the first to describe AMPK's critical role in mediating the actions of leptin, the hormone produced by fat cells that serves as a master regulator of neuroendocrine, metabolic, vascular, sympathetic and immune function. In 2002, Kahn demonstrated that AMPK is activated by leptin in skeletal muscle, thereby enabling the hormone to metabolize fatty acids. Subsequently, in 2004, her laboratory discovered that an opposing scenario takes place in the brain's hypothalamus, where AMPK is inhibited by leptin.
"Having determined that leptin's effects on food intake and body weight depend on the inhibition of AMPK in the hypothalamus, we wanted to determine the signaling events that were responsible for this effect," she explains.
The PI3K-AKT, mTOR-p70S6 kinase and AMPK pathways play distinct and critical roles in metabolic regulation, and each pathway is necessary for leptin's anorexigenic effects in the hypothalamus, which inhibit food intake. Through a series of experiments led by first author Yossi Dagon, PhD, a postdoctoral fellow in the Kahn lab, the scientific team showed that these pathways converge in an integrated phosphorylation cascade to mediate leptin action on the hypothalamus.
"Our findings identify a novel serine phosphorylation site on the AMPK alpha 2 catalytic subunit that mediates leptin's inhibitory effects and is critical for leptin action on food intake and body weight, and further show that ribosomal p70S6 kinase is an inhibitory AMPK kinase," says Kahn. 'These discoveries unify what were thought to be multiple parallel pathways affecting leptin action including PI3 kinase and AKT into a coordinated phosphorylation cascade."
Adds study coauthor Lewis Cantley, PhD, Director of BIDMC's Cancer Center and a leader in the field of cancer metabolism, "Since PI3K, AKT, mTOR and p70S6K have all been shown to be important in cancer biology, this integration of these pathways may be important for cancer and other human diseases and could lead to improved therapeutic approaches."
Obesity has reached epidemic proportions worldwide and increases the risk for developing diabetes, cardiovascular disease and early mortality. "Maintaining normal body weight requires tight control of energy homeostasis, which necessitates a constant flow of metabolic input to the hypothalamus in the form of nutrients and hormones," says Kahn. "Our new results have broad biologic implications, since mTOR-p70S6 kinase and AMPK have multiple, fundamental and generally opposing cellular effects that regulate metabolism, cell growth and development."
on July 03, 2012
at 02:18 PM
Without referring to studies and recalling basic biochemistry:
Leptin is secreted by adipose cells due to the action of insulin, which is secreted in response to an increase in blood glucose. Therefore leptin signals the 'fed state'.
PEPCK = Phosphoenolpyruvate carboxykinase => involved in gluconeogenesis (generation of glucose from amino acids, lactate and the glycerol moiety of triglycerides)
Given gluconeogenesis occurs at times when glucose is sparse there would be an inverse relationship between PEPCK and leptin, i.e. when leptin is up PEPCK is down.