👤 B Wichert

Obesity is an escalating global health problem affecting both humans and companion animals. In cats it is associated with increased mortality and multiple diseases, including diabetes mellitus. Two genes coding for proteins known to play a critical role in energy homeostasis across species are the proopiomelanocortin (POMC) gene and the melanocortin-4 receptor (MC4R) gene. A missense variant in the coding sequence of the feline MC4R (MC4R:c.92C>T) has been reported to be associated with diabetes and overweight in domestic shorthair cats, and while variants in the POMC gene are known to cause obesity in humans and dogs, variants in POMC and their association with feline obesity and diabetes mellitus have not been investigated to date. The current study aimed to assess the association between the previously described MC4R variant and body condition score (BCS), as well as body fat content (%BF) in 89 non-diabetic domestic shorthair cats. Furthermore, we investigated the feline POMC gene as a potential candidate gene for obesity. Our results indicate that the MC4R:c.92C>T polymorphism is not associated with BCS or %BF in non-diabetic domestic shorthair cats. The mutation analysis of all POMC exons identified two missense variants, with a variant in exon 1 (c.28G>C; p.G10R) predicted to be damaging. The variant was subsequently assessed in all 89 cats, and cats heterozygous for the variant had a significantly increased body condition score (p = 0.03) compared with cats homozygous for the wild-type allele. Results from our study provide additional evidence that the previously described variant in MC4R is not associated with obesity in domestic shorthair cats. More importantly, we have identified a novel variant in the POMC gene, which might play a role in increased body condition score and body fat content in domestic shorthair cats. Show less

Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2-/-) using online EEG recordings in living animals, behavioral assays and global gene expression profiling. EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2-/- mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and clock genes, particularly for SHARP1 and PER1. Our findings support the hypothesis that abnormal sleep and certain (endo)phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2. Show less

The circadian system provides the basis to anticipate and cope with daily recurrent challenges to maintain the organisms' homeostasis. De-synchronization of circadian feedback oscillators in humans causes 'jet lag', likely contributes to sleep-, psychiatric-, metabolic disorders and even cancer. However, the molecular mechanisms leading to the disintegration of tissue-specific clocks are complex and not well understood. Based on their circadian expression and cell culture experiments, the basic Helix-Loop-Helix (bHLH) transcription factors SHARP-1(Dec2) and SHARP-2(Stra13/Dec1) were proposed as novel negative regulators of the molecular clock. To address their function in vivo, we generated Sharp-1 and Sharp-2 single and double mutant mice. Our experiments reveal critical roles for both factors in regulating period length, tissue-specific control of clock gene expression and entrainment to external cues. Light-pulse experiments and rapid delays of the light-dark cycle (experimental jet lag) unravel complementary functions for SHARP-1 and SHARP-2 in controlling activity phase resetting kinetics. Moreover, we show that SHARP-1 and 2 can serve dual functions as repressors and co-activators of mammalian clock gene expression in a context-specific manner. This correlates with increased amplitudes of Per2 expression in the cortex and liver and a decrease in the suprachiasmatic nucleus (SCN) of double mutant mice. The existence of separate mechanisms regulating phase of entrainment, rhythm amplitude and period length has been postulated before. The differential effects of Sharp-deficiency on rhythmicity and behavioral re-entrainment, coupled to tissue-dependent regulatory functions, provide a new mechanistic basis to further understand the complex process of clock synchronizations. Show less