# Role for Glucose-Inhibited Orexin Neurons in Weight Regain Following Dieting

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $473,922

## Abstract

Scientific Abstract
Although a 10% weight loss significantly reduces the risk of obesity-associated diabetes and heart
disease, fewer than 20% of individuals achieve and maintain this weight loss. Thus, obesity underlies
a large portion of health care costs in the United States. Consumption of palatable foods above
homeostatic needs (reward-based feeding) is a likely contributor to weight regain. Ventral tegmental
area (VTA) dopamine neurons play a key role in reward-based feeding. Metabolic state influences
reward circuitry. However the mechanisms underlying this regulation are unclear. The lateral
hypothalamic area (LHA) orexin glucose-inhibited (GI) neurons which provide excitatory input to the
VTA dopamine neurons may be an important link between metabolic status and reward-based feeding.
For example, orexin mediates the fasting-induced increase in reward-based feeding. Our preliminary
data show that fasting also reduces the inhibitory effect of glucose on LHA orexin-GI neurons leading
to increased activation in low glucose. This proposal tests the hypothesis that weight loss increases
activation of LHA orexin-GI neurons by glucose deficit. This change in glucose sensitivity reinforces
reward-based feeding by causing persistent changes in glutamate signaling onto the VTA dopamine
neurons. As a result pre-prandial glucose decreases could enhance intake of the subsequent meal.
Three Specific Aims will test this hypothesis in vitro and in vivo: 1) Determine whether weight loss
enhances the response of orexin GI neurons to decreased glucose; 2) Determine whether weight loss
enhances synaptic plasticity in VTA dopamine neurons in a glucose and orexin dependent manner; 3)
Determine whether increased LHA glucose level attenuates the effects of fasting and weight loss on
reward based behavior. These studies will increase understanding of the mechanisms underlying
difficulties in achieving and maintaining weight loss.

## Key facts

- **NIH application ID:** 9977162
- **Project number:** 5R01DK103676-05
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Kevin D. Beck
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $473,922
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977162

## Citation

> US National Institutes of Health, RePORTER application 9977162, Role for Glucose-Inhibited Orexin Neurons in Weight Regain Following Dieting (5R01DK103676-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9977162. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*