Abstract
We have reported a correlation between hypothalamic expression of Creb-binding protein (Cbp) and lifespan, and that inhibition of Cbp prevents protective effects of dietary restriction during aging, suggesting that hypothalamic Cbp plays a role in responses to nutritional status and energy balance. Recent GWAS and network analyses have also implicated Cbp as the most connected gene in protein-protein interactions in human Type 2 diabetes. The present studies address mechanisms mediating the role of Cbp in diabetes by inhibiting hypothalamic Cbp using a Cre-lox strategy. Inhibition of hypothalamic Cbp results in profound obesity and impaired glucose homeostasis, increased food intake, and decreased body temperature. In addition, these changes are accompanied by molecular evidence in the hypothalamus for impaired leptin and insulin signaling, a shift from glucose to lipid metabolism, and decreased Pomc mRNA, with no effect on locomotion. Further assessment of the significance of the metabolic switch demonstrated that enhanced expression of hypothalamic Cpt1a, which promotes lipid metabolism, similarly resulted in increased body weight and reduced Pomc mRNA.
Highlights
The growing prevalence of type 2 diabetes associated with obesity constitutes one of the greatest threats to world health in the 21st century [1], but mechanisms contributing to these syndromes remain to be elucidated
To study the role of hypothalamic Creb-binding protein (Cbp) on energy balance, AAV-Cre-recombinase or control AAV-GFP was infused directed towards the ventromedial hypothalamus (1μl per side) of Cbpflox/flox mice
Mice were infused and housed singly on a standard chow diet (NIH-31). This protocol resulted in a significant reduction of hypothalamic Cbp mRNA levels (41%) and CBP-immunopositive cells (74%) as indicated by immunohistochemistry using a CBP-specific antibody (Fig 1A–1C)
Summary
The growing prevalence of type 2 diabetes associated with obesity constitutes one of the greatest threats to world health in the 21st century [1], but mechanisms contributing to these syndromes remain to be elucidated. Recent GWAS and network analyses have implicated Cbp as the most connected gene in protein-protein interactions in Type 2 diabetes [10] These reports suggest a function for Cbp in nutrient sensing and energy balance. The present studies examined the role of hypothalamic Cbp in energy balance and glucose homeostasis These studies demonstrate that inhibition of hypothalamic Cbp produces robust obese phenotypes entailing both increased food intake and reduced body temperature, associated with impaired glucose homeostasis. Further supporting a causal role, we demonstrate that enhanced hypothalamic expression of carnitine palmitoyltransferase 1A (Cpt1a), a key enzyme promoting lipid metabolism, produces similar obese phenotypes, associated with reduced hypothalamic of hypothalamic Pro-opiomelanocorticotropin (Pomc). These studies demonstrate that reduced hypothalamic Cbp promotes obese phenotypes, plausibly in part by enhancing hypothalamic lipid metabolism and reducing hypothalamic glucose metabolism, associated with reduced hypothalamic Pomc
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