Late-Onset Leanness in Mice with Targeted Ablation of Melanin Concentrating Hormone Neurons

Abstract

The observation that loss of orexin (hypocretin) neurons causes human narcolepsy raises the possibility that other acquired disorders might also result from loss of hypothalamic neurons. To test this possibility for body weight, mice with selective loss of melanin concentrating hormone (MCH) neurons were generated. MCH was chosen to test because induced mutations of the MCH gene in mice cause hypophagia and leanness. Mice with ablation of MCH neurons were generated using toxin (ataxin-3)-mediated ablation strategy. The mice appeared normal but, after 7 weeks, developed reduced body weight, body length, fat mass, lean mass, and leptin levels. Leanness was characterized by hypophagia and increased energy expenditure. To study the role of MCH neurons on obesity secondary to leptin deficiency, we generated mice deficient in both ob gene product (leptin) and MCH neurons. Absence of MCH neurons in ob/ob mice improved obesity, diabetes, and hepatic steatosis, suggesting that MCH neurons are important mediators of the response to leptin deficiency. These data show that loss of MCH neurons can lead to an acquired leanness. This has implications for the pathogenesis of acquired changes of body weight and might be considered in clinical settings characterized by substantial weight changes later in life.

Pmchexpression during early development is critical for normal energy homeostasis

“…As it is unknown if the metabolic activity of WAT is altered in pmch Ϫ/Ϫ rats and as it has been demonstrated that WAT has a minimal contribution to EE (13), we chose to show EE not normalized, normalized for lean mass, and normalized for body weight. EE data normalized for body weight showed increased or a trend toward increased EE levels in pmch Ϫ/Ϫ rats compared with pmch ϩ/ϩ rats, which is in line with findings that oxygen consumption levels are increased in MCH Ϫ/Ϫ mice if normalized for body weight (1,59). However, EE not normalized or EE normalized for lean mass showed decreased or a trend toward decreased levels in pmch Ϫ/Ϫ rats compared with pmch ϩ/ϩ rats.…”

“…Relative Fto expression in pmch Ϫ/Ϫ rats was decreased at PND 40 and increased at PND 100 compared with pmch ϩ/ϩ rats, while relative expression of Pomc and Hcrt was normal at PND 40 but was decreased and increased, respectively, in pmch Ϫ/Ϫ rats compared with pmch ϩ/ϩ rats at PND 100. The expression profiles of Npy and Agrp in adult rats confirm findings in adult mice; however, the expression profiles of Pomc and Hcrt either partially agree or disagree with findings in adult mice (1,59). In summary, the time-related differences in expression profiles and a likely interaction between Pmch and the orexigenic and anorectic systems studied here could offer an explanation to the sudden stabilization of relative body weight but remain to be studied in more detail.…”

“…Increased oxygen consumption has been shown for 20-wk-old mice with a loss of Pmch and 17-wk-old transgenic mice with a severe loss of MCH neurons (1,59). It is however important to note that in both situations data were normalized for body weight.…”

Effects of intracerebroventricular and intra-accumbens melanin-concentrating hormone agonism on food intake and energy expenditure

“…Hypothalamic expression of MCH mRNA is upregulated during starvation in lean mice, as well as in genetically obese ob/ob mice (30), and MCH overexpression leads to obesity and to an increased susceptibility to high-fat feeding (19). In addition, acute or chronic intracerebroventricular administration of MCH or MCHR1 agonists stimulate feeding in rats and mice (11,15,30,32,36), while ablations of MCH (35,37), MCH neurons (2), and MCHR1 (9,21) have all been reported to promote fat loss mainly by increasing energy expenditure.…”

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

“…The observations that mice with overexpression of MCH1-R are obese, MCH1-R knockout animals become lean and can develop a hypophagia [208,209] and leaness may occur also in consequence to ablation of melanin-concentrating hormone neurons [210] accelerated the efforts in search for suitable antagonistic agents up to date. Among these GW 856464 [211], AMG076 [212] and NGD-4715 [213] achieved phase 1 clinical investigations.…”