title: LMO4 is essential for paraventricular hypothalamic neuronal activity and calcium channel expression to prevent hyperphagia.
abstract: 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 LMO4-deficient PVH neurons showed reduced basal cellular excitability together with reduced voltage-activated Ca(2+) currents. Real-time PCR quantification revealed that LMO4 regulates the expression of Ca(2+) channels (Cacna1h, Cacna1e) 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 LMO4-deficient mice. Together, these results demonstrate that reduced neural activity in LMO4-deficient PVH neurons accounts for hyperphagia. Thus, maintaining PVH activity is important to prevent hyperphagia-induced obesity.
authors.affiliation: Center for Stroke Recovery, Ottawa Hospital Research Institute and University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, and University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
authors.forename: Tariq
authors.initials: T
authors.lastname: Zaman
authors.forename: Xun
authors.initials: X
authors.lastname: Zhou
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Pandey
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Qin
authors.forename: Kianoosh
authors.initials: K
authors.lastname: Keyhanian
authors.forename: Kendall
authors.initials: K
authors.lastname: Wen
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Courtney
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.forename: Hsiao-Huei
authors.initials: HH
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D015220:Calcium Channels / Q000096:biosynthesis; D020908:Calcium Channels, R-Type / Q000096:biosynthesis*; D020747:Calcium Channels, T-Type / Q000096:biosynthesis*; D027682:Cation Transport Proteins / Q000096:biosynthesis*; D004435:Eating / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D006963:Hyperphagia / Q000378:metabolism* / Q000517:prevention & control*; D060588:LIM Domain Proteins / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C498916:Cacna1e protein, mouse; C504883:Cacna1h protein, mouse; D015220:Calcium Channels; D020908:Calcium Channels, R-Type; D020747:Calcium Channels, T-Type; D027682:Cation Transport Proteins; D060588:LIM Domain Proteins; C491976:Lmo4 protein, mouse