# Circadian Neuronal Basis for Obesity and Diabetes

> **NIH NIH K99** · NORTHWESTERN UNIVERSITY · 2020 · $91,500

## Abstract

The present public health threat in diabetes mellitus and metabolic syndrome remains strongly linked to the
epidemic of obesity in the US. At the pathophysiologic level, exciting studies from our group have been at the
forefront in establishing circadian disruption as a novel risk factor for obesity and diabetes mellitus.
Remarkably, animals provided a high-fat diet exhibit profound disruption in both molecular and behavioral
circadian rhythms, and shiftwork and sleep loss has been associated with obesity and metabolic syndrome in
humans, but our understanding of the mechanisms interconnecting circadian disruption with obesity and
metabolic comorbidities remains in its infancy. The circadian system is organized hierarchically with brain
pacemaker cells controlling metabolic cycles in peripheral cells. Recently, our genetic and genomic work has
established an essential role of the molecular clock in the rhythmic regulation of hunger and peripheral glucose
homeostasis through the control of NPY/AgRP neurons, revealing a requirement for the clock in energy
sensing at the level of brain, and in turn, pinpointing brain clock pathologies as a factor in metabolic disease.
Through stereotactic targeting, we find that clock gene ablation specifically within “pacemaker” neurons causes
profound obesity, due to abrogated signaling to major regions involved in the regulation of body weight,
metabolism and thermogenesis. The forward-looking goal of this career development application is to apply
physiological, genetic, and behavioral approaches to determine mechanisms through which circadian
disruption contributes to obesity and diabetes, with a specific focus on how disruption of circadian-energy
neuron neurocircuitry leads to hyperphagia, weight gain, peripheral insulin resistance, liver fat accumulation,
and impaired glucose disposal in skeletal muscle. Building on an expert neuroscientific and metabolic
collaborative network the approach is to utilize a combination of chemogenetic targeting to control activity of
the clock-energy neuron circuit, thereby simulating the effect of jetlag and sleep disruption on whole-body
metabolism. Molecular profiling will be utilized to identify circadian signals that control hunger neuron activity
and peripheral glucose metabolism, and to develop behavioral and genetic interventions to reduce body weight
in animal models of obesity. By first honing the above techniques, the proposed projects will enable the
applicant to subsequently employ this unique set of approaches in the R00 phase, in clinically relevant models
of weight loss and regain, to uncover the role of circadian rhythm disruption in successful long-term weight loss
and as an intervention to increase insulin sensitivity and treat diabetes. As such, this work has direct
translational implications for public health, for understanding how chronic disruption of the circadian system –
as experienced in shift work, jet lag and artificial light exposure at night – ma...

## Key facts

- **NIH application ID:** 9953717
- **Project number:** 1K99DK124682-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Jonathan Cedernaes
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $91,500
- **Award type:** 1
- **Project period:** 2020-08-24 → 2022-08-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953717

## Citation

> US National Institutes of Health, RePORTER application 9953717, Circadian Neuronal Basis for Obesity and Diabetes (1K99DK124682-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9953717. Licensed CC0.

---

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