Responsiveness of hypothalamo-pituitary-adrenal axis to leptin is impaired in diet-induced obese rats

Andrew C. Shin,Andrew Woolcock,Puliyur S. MohanKumar,Michelle James,Katrina Linning,Sheba M. J. MohanKumar,Priya Balasubramanian,Madhu P. Sirivelu

doi:10.1038/s41387-019-0076-y

Andrew C. Shin, Andrew Woolcock + Show 6 more

Open Access

https://doi.org/10.1038/s41387-019-0076-y

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Abstract

Background/objectivesDiet-induced obese (DIO) rats have altered stress (HPA) axis activity compared to diet-resistant (DR) rats when chronically exposed to a high-fat (HF) diet. Since stress axis is tightly regulated by leptin, an adipocyte-secreted hormone that is important for controlling body weight, we hypothesized that leptin action is impaired in DIO rats leading to alterations in HPA axis activity.Subjects/methodsWe intraperitoneally injected selectively bred DIO and DR rats with either saline or recombinant rat leptin. HPA axis activity was assessed by measuring norepinephrine (NE) in the paraventricular nucleus (PVN), corticotropin-releasing hormone (CRH) in the median eminence, and serum corticosterone (CORT). To test if HF exposure duration and the corresponding increase in leptin differentially affects HPA axis activity, we placed animals on a chow or HF diet for 1 or 6 weeks.ResultsLeptin injection significantly increased serum leptin levels in both DIO and DR animals. It also reduced PVN NE in both groups, indicating that noradrenergic neurons in both groups remain responsive to leptin. HF diet duration-dependently increased serum leptin only in DIO animals whereas PVN NE increased in both groups. While DR rats responded to HF diet by increasing CRH and CORT at both time-points, responses in DIO rats varied, suggesting that they have altered HPA axis activity that may be dependent on HF-induced leptin levels and/or signaling. To understand the underlying mechanisms, we measured pSTAT-3, a marker of leptin signaling, in brainstem noradrenergic neurons and found reduced pSTAT-3 in A1 region of HF-fed DIO rats. We also found higher serum free fatty acids (FFAs) and a pro-inflammatory cytokine, IL-1β.ConclusionsCollectively, these findings reveal that DIO rats have inherent neuroendocrine impairment in NE-HPA axis circuitry that worsens with the extent of HF diet exposure, possibly due to brainstem leptin resistance and/or elevated circulating FFAs and IL-1β.

Highlights

Diet-induced obesity (DIO) is a serious health condition that has been affecting individuals of all ages
While DR rats responded to HF diet by increasing corticotropin-releasing hormone (CRH) and CORT at both time-points, responses in DIO rats varied, suggesting that they have altered HPA axis activity that may be dependent on HF-induced leptin levels and/or signaling
Collectively, these findings reveal that DIO rats have inherent neuroendocrine impairment in NE-HPA axis circuitry that worsens with the extent of HF diet exposure, possibly due to brainstem leptin resistance and/or elevated circulating free fatty acids (FFAs) and IL-1β

Summary

Introduction

Diet-induced obesity (DIO) is a serious health condition that has been affecting individuals of all ages. Activation of the stress axis involves increased noradrenergic outflow to the paraventricular nucleus of the hypothalamus (PVN) that contains corticotropin-releasing hormone (CRH) neurons. Since stress plays a key role in driving anabolism, we had suspected that high-fat (HF) diet would further stimulate the stress axis, contributing to the perpetuation of a vicious cycle leading to diet-induced obesity. Our previous work demonstrated that HF feeding for 6 weeks does not increase stress axis activity, but rather induces characteristic dysregulation of the stress axis in DIO rats[3]. HF feeding increased NE levels in the PVN of DIO rats, but failed to produce a corresponding increase in CRH and CORT as demonstrated in dietresistant (DR) rats

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