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A novel hypothalamic protein regulated by high fat diet and leptin

Published online by Cambridge University Press:  03 June 2015

D. Sergi ,
A. C. Morris ,
J. E. Drew ,
F. M. Campbell ,
P. Nicol  and
L. M. Williams
D. Sergi
Affiliation:
Rowett Institute of Nutrition and Health, Greenburn road, AB21 9SB, University of Aberdeen
A. C. Morris
Affiliation:
Rowett Institute of Nutrition and Health, Greenburn road, AB21 9SB, University of Aberdeen
J. E. Drew
Affiliation:
Rowett Institute of Nutrition and Health, Greenburn road, AB21 9SB, University of Aberdeen
F. M. Campbell
Affiliation:
Rowett Institute of Nutrition and Health, Greenburn road, AB21 9SB, University of Aberdeen
P. Nicol
Affiliation:
Rowett Institute of Nutrition and Health, Greenburn road, AB21 9SB, University of Aberdeen
L. M. Williams
Affiliation:
Rowett Institute of Nutrition and Health, Greenburn road, AB21 9SB, University of Aberdeen
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Abstract

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Obesity is a global health issue. Treatment or prevention of obesity via lifestyle change remains elusive, particularly due to the lack of patient compliance and the subsequent weight regain following the cessation of dietary intervention. The hypothalamus is pivotal in regulating energy homeostasis by matching up energy intake and expenditure. Therefore, identifying novel mechanisms underlying these processes will provide new insights into the treatment of obesity. High-fat feeding has been reported to induce functional and structural impairment of the hypothalamus( Reference Thaler, Yi and Schur 1 – Reference Zhang, Zhang and Zhang 3 ) leading to leptin( Reference Koch, Lowe and Pretz 4 ) as well as ghrelin resistance( Reference Briggs, Enriori and Lemus 5 ). As a consequence regulation of energy homeostasis is disrupted.

Microarray analysis identified a novel gene, SerpinA3N, highly up regulated in hypothalamic neurons of mice in response to consumption of a high-fat diet (HFD) and intraperitoneal (IP) injections of leptin( Reference Williams, Grant and Morris 6 ). We sought to investigate whether SerpinA3N plays a role in energy balance by using a hypothalamic cell line model.

Initial results confirm that SerpinA3N is expressed in the hypothalamic neuronal cell line as assessed by PCR (Fig. 1). Its expression is up regulated by both leptin (P < 0·001) and palmitic acid (P < 0·001) challenge (Fig. 2). Statistical analysis was carried out using one-way ANOVA.

Fig. 1.

Electrophoresis on 1% agarose of SerpinA3N PCR product amplified using specific primers. Product size 1·02 kb.

Fig. 2.

SerpinA3N gene expression in the hypothalamic neuronal cell line in response to palmitic acid and leptin. Gene expression normalized to B2M. Fold change relative to vehicle treated cells. ***P < 0·001

Western blot revealed that alpha-1-antichymotrypsin (the protein encoded by SerpinA3) is secreted into the cell culture medium. Further studies are required to identify its role in hypothalamus as well as its downstream target(s) and post-translational modifications.

References

1. Thaler, JP, Yi, CX, Schur, EA, et al. (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122, 153–162.CrossRefGoogle Scholar
2. Milanski, M, Degasperi, G, Coope, A, et al. (2009) Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci 29, 359–370.CrossRefGoogle ScholarPubMed
3. Zhang, X, Zhang, G, Zhang, H, et al. (2008) Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61–73.CrossRefGoogle ScholarPubMed
4. Koch, CE, Lowe, C, Pretz, D, et al. (2014) High-fat diet induces leptin resistance in leptin-deficient mice. J Neuroendocrinol 26, 58–67.CrossRefGoogle ScholarPubMed
5. Briggs, DI, Enriori, PJ, Lemus, MB, et al. (2010) Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology 151, 4745–4755.CrossRefGoogle ScholarPubMed
6. Williams, LM, Grant, C, Morris, AC, et al. SerpinA3N expression in the hypothalamus is regulated by nutritional status, age and leptin. (Neuroscience conference Washington 2014).Google Scholar
Figure 0

Fig. 1. Electrophoresis on 1% agarose of SerpinA3N PCR product amplified using specific primers. Product size 1·02 kb.

Figure 1

Fig. 2. SerpinA3N gene expression in the hypothalamic neuronal cell line in response to palmitic acid and leptin. Gene expression normalized to B2M. Fold change relative to vehicle treated cells. ***P < 0·001