Elsevier

Neurobiology of Aging

Volume 35, Issue 5, May 2014, Pages 1153-1161
Neurobiology of Aging

Regular article
Metabolic abnormalities and hypoleptinemia in α-synuclein A53T mutant mice

https://doi.org/10.1016/j.neurobiolaging.2013.10.088Get rights and content

Abstract

Parkinson's disease (PD) patients frequently display loss of body fat mass and increased energy expenditure, and several studies have outlined a relationship between these metabolic abnormalities and disease severity, yet energy metabolism is largely unstudied in mouse models of PD. Here we characterize metabolic and physiologic responses to a high calorie diet (HCD) in mice expressing in neurons a mutant form of human α-synuclein (A53T) that causes dominantly inherited familial forms of the disease. A53T (SNCA) and wild type (WT) littermate mice were placed on a HCD for 12 weeks and evaluated for weight gain, food intake, body fat, blood plasma leptin, hunger, glucose tolerance, and energy expenditure. Results were compared with both SNCA and WT mice on a control diet. Despite consuming similar amounts of food, WT mice gained up to 66% of their original body weight on a HCD, whereas SNCA mice gained only 17%. Further, after 12 weeks on a HCD, magnetic resonance imaging analysis revealed that WT mice had significantly greater total and visceral body fat compared with SNCA mice (p < 0.007). At the age of 24 weeks SNCA mice displayed significantly increased hunger compared with WT (p < 0.03). At the age of 36 weeks, SNCA mice displayed significant hypoleptinemia compared with WT, both on a normal diet and a HCD (p < 0.03). The HCD induced insulin insensitivity in WT, but not SNCA mice, as indicated by an oral glucose tolerance test. Finally, SNCA mice displayed greater energy expenditure compared with WT, as measured in a Comprehensive Laboratory Animal Monitoring System, after 12 weeks on a HCD. Thus, SNCA mice are resistant to HCD-induced obesity and insulin resistance and display reduced body fat, increased hunger, hypoleptinemia and increased energy expenditure. Our findings reveal a profile of metabolic dysfunction in a mouse model of PD that is similar to that of human PD patients, thus providing evidence that α-synuclein pathology is sufficient to drive such metabolic abnormalities and providing an animal model for discovery of the underlying mechanisms and potential therapeutic interventions.

Introduction

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor symptoms including a resting tremor, bradykinesia, and rigidity. These symptoms are related to degeneration of dopaminergic neurons in the substantia nigra (Crabtree and Zhang, 2012). Pathologically, PD brains show accumulation of α-synuclein in structures termed “Lewy bodies” and loss of dopaminergic neurons in the substantia nigra (Polymeropoulos et al., 1997). Overexpression of mutant α-synuclein is commonly used to induce parkinsonism-like pathology and symptoms in mouse models of PD (Crabtree and Zhang, 2012, Lin et al., 2012). In addition to the primary motor dysfunctions commonly described in PD, many nonmotor symptoms are present and can appear before the onset of motor abnormalities. Chief among these are increases in anxiety, autonomic nervous system dysfunction, alterations in normal sleep patterns, dementia, deficits in olfaction, and weight loss (Gallagher and Schrag, 2012, Rothman and Mattson, 2012). Though rare, some cases of PD are caused by specific genetic defects including mutations in the genes encoding α-synuclein, parkin, LRRK2, PINK1, and DJ-1 (Corti et al., 2011). These different mutations may compromise mitochondrial function and/or protein clearance mechanisms in vulnerable neuronal populations (Cookson and Bandman, 2010).

Unintended weight loss is commonly observed in PD patients (Chen et al., 2003, Levi et al., 1990, Lorefalt et al., 2004, Markus et al., 1993). Studies show this weight loss represents loss of body fat mass rather than muscle mass and that weight loss is correlated to increased severity of motor symptoms. This implies that weight loss, or alterations in energy metabolism, may be directly related to the clinical severity of PD (Levi et al., 1990, Markus et al., 1993). A recent study also showed that PD patients who displayed a decreased body mass index (BMI) showed poorer cognitive function and faster rate of cognitive decline than PD patients who displayed a stable BMI, further implying a relationship between disease severity and weight and/or metabolic stability (Kim et al., 2012).

There are several hypotheses to explain unintended weight loss in PD patients, including decreased energy intake, increased energy expenditure, constipation, changes in physical activity, or dysregulation of circulating leptin levels (Delikanaki-Skaribas et al., 2009, Lorefalt et al., 2004, Lorefält et al., 2009). Using a ventilated hood technique, Levi et al. (1990) measured increased energy expenditure in PD patients compared with control subjects. A similar study of energy expenditure using the doubly labeled water technique also measured increased daily energy expenditure in PD patients who exhibited weight loss compared with those who did not (Delikanaki-Skaribas et al., 2009). Further, one study showed that PD patients who lost weight were found to have an increased energy intake and a lower leptin level than those who did not lose weight, implying that reductions in circulating leptin are responsible for increased appetite and energy intake (Lorefält et al., 2006, Lorefält et al., 2009). Other studies have shown hypoleptinemia in PD patients, particularly those experiencing unintended weight loss, raising the possibility that unintended weight loss in PD patients may be because of abnormal leptin signaling (Evidente et al., 2001, Lorefält et al., 2009). Despite the emergence of a relationship between disease severity and metabolic dysfunction and clinical evidence of a role for altered metabolism in PD, no study to date has evaluated energy metabolism in a mouse model of PD.

In line with data regarding changes in energy expenditure and metabolism, a small number of studies have outlined associations between PD and diabetes. Some studies indicate a greater incidence of diabetes in PD patients compared with the general population or an increased risk of developing PD in diabetic patients (Driver et al., 2008, Hu et al., 2007, Sandyk, 1993). However, at least one study showed that the risk of developing incident diabetes was lower for PD patients than for patients without (Becker et al., 2008). More compellingly, D'Amelio et al. (2009) measured an inverse association between PD and diabetes that preceded the onset of PD, implying that metabolic alterations may appear before PD symptoms and may include resistance to the development of glucose intolerance. It is noteworthy that drugs frequently used to treat PD, such as levodopa, are hyperglycemic and may therefore confound clinical associations measured between PD and diabetes in patients under treatment for PD (Sirtori et al., 1972).

However, despite clinical evidence for potential metabolic dysfunction in PD and the probability that such metabolic alterations are related to PD symptoms, no study to date has outlined a metabolic phenotype in a rodent model of PD. The present study uses a high calorie diet (HCD) in a mouse model of PD to outline dramatic alterations in metabolism compared with wild-type (WT) controls including resistance to high calorie diet-induced obesity and insulin resistance, hypoleptinemia, increased hunger, and increased energy expenditure. The HCD was chosen as a stimulus known to induce weight gain, increase in body fat, leptin, and insulin resistance in normal mice. Results in this mouse model of PD demonstrated a strong metabolic phenotype that mimics that noted clinically in PD patients and may be a useful model for understanding the interactions between α-synuclein pathology and perturbed energy metabolism in PD.

Section snippets

Mice and experimental timelines

Animal care and experimental procedures followed National Institutes of Health guidelines and were approved by the National Institute on Aging Animal Care and Use Committee. Mice transgenic for the A53T mutation of the human α-synuclein (SNCA) gene under the control of a human Thy1 (thymus cell antigen 1, theta) promoter were purchased from Jackson laboratories (Bar Harbor, ME, USA) and bred at the National Institute on Aging. Male SNCA mice and wild-type littermates were used in separate

SNCA mice are resistant to high calorie diet-induced obesity

In the present study, mice were fed a diet high in simple sugars and saturated fats and their drinking water was supplemented with high-fructose corn syrup (Fig. 1A). This diet has been shown to increase fasting blood glucose levels and serum cholesterol and triglycerides in normal mice and exacerbates dysfunction of the autonomic nervous system in SNCA mice (Griffioen et al., 2013; Stranahan et al., 2008). Our results show that, starting at the age of 12 weeks, wild-type mice gain on average

Discussion

This study demonstrates clinically-relevant metabolic dysfunction in a mouse model of PD. Results showed that mice over-expressing the A53T α-synuclein mutation under the control of the Thy1 promoter were resistant to both high fat diet-induced obesity and high fat diet-induced insulin resistance, displayed hypoleptinemia, greater hunger and lower body fat volume and higher oxygen consumption and energy expenditure. These robust metabolic abnormalities closely mirror those seen in clinical

Disclosure statement

The authors have no actual or potential conflicts of interest.

Acknowledgements

This research was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The authors thank Catherine Crews and Charles Reitz for assistance with management of the mouse colonies.

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    Authors contributed equally to this work.

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