Zaman Mirzadeh, MD, PhD, Barrow Neurological Institute, presented a broad overview on brain defense of glycemia in health and diabetes to start off the ADA Diabetes Journal Symposium—It Is All in Your Head—Central Nervous System Control of Systemic Metabolism.
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Elevated glucose levels result in insulin release from beta cells, which are glucose sensing, and that has actions on various organs to restore euglycemia. The central nervous system (CNS) is an essential element in a holistic model of glucose homeostasis, Dr. Mirzadeh said.
He used an example of cold exposure responses and how they exemplify CNS-based homeostasis. The nervous system coordinates thermoregulation, glucose homeostasis, and energy balance.
“[The CNS] is engaging each of these different systems, and it’s doing it in a more prospective, anticipatory way, rather than waiting for these metabolic variables to dramatically change, before some negative feedback signal is able to elicit these,” Dr. Mirzadeh said. “We want to keep them stable; that’s the whole point.”
Ultimately, the brain integrates sensory signals of circulating glucose levels with interoceptive signals of an individual’s metabolic state, such as what is happening in the environment and what the person’s planned behaviors are that might need glucose, Dr. Mirzadeh explained. The CNS then provides descending modulation of insulin-dependent and insulin-independent mechanisms.
Kevin Williams, PhD, University of Texas Southwestern Medical Center, discussed CNS regulation of systemic glucose and the lessons learned from adaptation to exercise, specifically in the hypothalamus and arcuate nucleus.
Hypothalamic pro-opiomelanocortin (POMC) and neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons in the brain regulate feeding, energy expenditure and glucose metabolism, he explained. These neurons are highly malleable to a variety of conditions and challenges, including exercise. He studied whether exercise could induce a measurable change in synaptic activity and cellular properties of arcuate POMC or NPY/AgRP neurons, as well as whether those changes were reversible.
In animal studies, there was evidence of change in neurons after high-intensity intermittent exercise. It activated POMC neurons and inhibited NPY/AgRP neurons. Those changes were reversible within hours in NPY neurons and within 48 hours in POMC neurons.
“This activity profile is also in agreement with an improvement in insulin sensitivity or an improvement in glucose metabolism,” Dr. Williams said.
There are several mechanisms that affect those changes, including modification of synaptic inputs and outputs, temperature, and sex- or circadian-dependent effects.
“[Exercise] could induce the plasticity of this circuit, resulting in some type of a hypothalamic long-term potentiation (LTP) that can improve some kind of a metabolic state,” Dr. Williams said. “This could ultimately affect other cell populations, but our data also suggests that these other cell populations are influencing this hypothalamic LTP. And we really want to try and identify what this factor is that could be contributing to these changes that is unclear right now.”
Kristy L. Townsend, PhD, The Ohio State University, discussed neural signaling to and from adipose tissue in the regulation of metabolic health. Dr. Townsend focused on peripheral neuropathy, a loss of innervation, and blunted neural communication between tissues and brain. Diabetes is the No. 1 cause.
Her lab has been focused on the neuropathy in adipose tissues, which has been observed in mouse and human tissues with obesity, diabetes, and aging.
“We think when we undergo adipose neuropathy, this could also exacerbate metabolic disease by reducing that important bidirectional neural communication with the brain,” she said.
Her lab is studying neuro-adipose nexus (NAN), one of the nerve structures in adipose tissue, and how they change in response to energy status. They increase with high-fat diets as well as during aging.
Aging has numerous negative impacts on adipose tissue, metabolic health and the nervous system. One study found that 17aEstradiol improved age-related nerve/metabolic phenotypes in both male and female mice. Skin neuropathy that was observed in other treatments was completely improved in both sexes with Estradiol, as well as improvement in glucose tolerance and neuromuscular function.
“We are excited about it as a potential therapy for peripheral neuropathy and potentially linking estrogen-receptor signaling on nerves to metabolic improvements,” Dr. Townsend concluded.
Laura Rupprecht, PhD, Postdoctoral Scholar at Duke University School of Medicine, also spoke about what the gut communicates to the brain about food.
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