Mouse models for the central melanocortin system

Abstract

Obesity is characterized by an excess storage of body fat and promotes the risk for complex disease traits such as diabetes mellitus and cardiovascular diseases. The obesity prevalence in Europe is rising and meanwhile ranges from 10 to 20% in men and 15-25% in women. Body fat accumulation occurs in states of positive energy balance and is favored by interactions among environmental, psychosocial and genetic factors. Energy balance is regulated by a complex neuronal network of anorexigenic and orexigenic neurons which integrates peripheral and central hormonal and neuronal signals relaying information on the metabolic status of organs and tissues in the body. A key component of this network is the central melanocortin pathway in the hypothalamus that elicits metabolic and behavioral adaptations for the maintenance of energy homeostasis. Genetic defects in this system cause obesity in mice and humans. In this review we emphasize mouse models with spontaneous natural mutations as well as targeted mutations that contributed to our understanding of the central melanocortin system function in the control of energy balance.Keywords Energy balance Á Melanocortin Á Mouse models Á Obesity ObesityObesity is characterized by an excess of body fat and promotes the risk for the development of complex disease traits like diabetes mellitus, cardiovascular dysfunctions, certain forms of cancer and sleep-breathing disorders. World Health Organization defines obesity by a body mass index (BMI) larger than 30 kg/m 2 , whereas overweight is defined by a BMI between 25 and 29.9 kg/m 2 . The obesity prevalence in Europe ranges from 10 to 20% in men and 15-25% in woman. Body fat mass is influenced by interactions among environmental, psychosocial and genetic factors. Promotion of positive energy balance causes obesity in humans as well as in mice (for review see [4,20,33]).The mouse has proven itself as an excellent model for investigations on human diseases as development and genetics are similar in mouse and man. Furthermore, genetic engineering techniques in the mouse became wellestablished and reliable tools in the last two decades. In this mini review we highlight different mouse models which have been instrumental to study body weight regulation and the development of obesity.The melanocortin system and its role in the regulation of energy homeostasisThe lipostatic hypothesis for the control of food intake postulates that adipose tissue produces a hormone in proportion to the amount of fat and acts on the central nervous system to reduce feeding and increase energy expenditure for maintaining energy balance [32].

The melanocortin action is biased toward protection from weight loss in mice

“…In line with our observations, within the rather rich literature on the extensively studied POMC and MC4R neurons, the vast majority of studies report an obese rather than a lean phenotype 57 . Animal models with a gain of function of orexigenic AgRP neurons develop obesity, while those with loss of function have no impact on body weight 43,[58][59][60] .…”

Deficiency of Lipoprotein Lipase in Neurons Modifies the Regulation of Energy Balance and Leads to Obesity

“…The increased expression of Mc3r could very well be a compensatory effect of the substantially increased gene expression of AgRP in the hypothalamus, which seems to have no effect on Mc4r expression. Compared to the important role of the Mc4r in regulating food intake and the CNS regulation of glucose homeostasis, the biological function of the Mc3r is not well established (Bolze and Klingenspor, 2009; Lee and Wardlaw, 2007). Mc3r is often co-localized with Mc4r, and in some cases might share redundant functions as Mc4r, but accumulating data show that its precise function in obesity, cachexia, and related feeding behaviors might involve unique signaling pathways and/or regulatory mechanisms.…”

Hypothalamic GPCR Signaling Pathways in Cardiometabolic Control

“…Functionally, ARC POMC neurons release MC4R agonist alpha-melanocyte stimulating hormone (α-MSH), leading to reduced food intake and increased energy expenditure ( Kim et al, 2000 ; Atasoy et al, 2012 ; Zhan et al, 2013 ; Dodd et al, 2015 ), whereas ARC AgRP neurons release the MC4R inverse agonist AgRP, leading to the opposite physiological outcomes ( Aponte et al, 2011 ; Atasoy et al, 2012 ). MC4R mutations represent the most prevalent form of monogenic obesity ( Farooqi et al, 2003 ) and both animal models and human patients carrying loss-of-function MC4R mutations exhibit early-onset obesity caused by hyperphagia and reduced energy expenditure ( Bolze and Klingenspor, 2009 ; Kuhnen et al, 2019 ; Rene et al, 2021 ).…”