LM04 Is Essential for Paraventricular Hypothalamic Neuronal Activity and Calcium Channel Expression to Prevent Hyperphagia.

The dramatic increase in the prevalence of obesity reflects a lack of progress in combating one of the most serious health problems of this century. Recent studies have improved our understanding of the appetitive network by focusing on the paraventricular hypothalamus (PVH), a key region responsible for the homeostatic balance of food intake. Here we show that mice with PVH-specific ablation of LIM domain only 4 (Lmo4) become rapidly obese when fed regular chow due to hyperphagia rather than to reduced energy expenditure. Brain slice recording of LM04-deficient PVH neurons showed reduced basal cellular excitability together with reduced voltage-activated Ca2+ currents. Real-time PCR quantification revealed that LM04 regulates the expression of Ca2+ channels (Cacnalh, Cacnale) that underlie neuronal excitability. By increasing neuronal activity using designer receptors exclusively activated by designer drugs technology, we could suppress food intake of PVH-specific LM04-deficient mice. Together, these results demonstrate that reduced neural activity in LM04-deficient PVH neurons accounts for hyperphagia. Thus, maintaining PVH activity is important to prevent hyperphagia-induced obesity. [ABSTRACT FROM AUTHOR]