Critical Conversations: Fat, Brain, and Regulation of Energy Balance

Highlights from the 2005 Banting Lecture
Jeffrey S Flier, MD

Reported by Kimberly McFarland, PhD

Dr Flier began with a reminder of the relationship between type 2 diabetes and obesity. As an example, he cited the Nurses’ Health Study in which the risk of type 2 diabetes was very low in the absence of obesity. Adipose tissue acts as an endocrine organ, producing a variety of signaling agents including: estrogen; free fatty acids (FFA); adipsin; TNF-alpha and other inflammatory cytokines; angiotensinogen; cortisol; and the adipokines, adiponectin, resistin, and leptin. Leptin signaling in the brain has been a focus of Dr Flier’s research.

Leptin levels increase in obese individuals, but leptin signaling is reduced in response to a high fat diet. These observations suggest that a high fat diet may lead to the development of leptin resistance. Leptin activates the protein, SOCS-3 (suppressor of cytokine signaling -3), in a subset of hypothalamic neurons. Following activation, SOCS-3 acts as a negative feedback signal for leptin by binding to and inhibiting signaling through specific leptin receptors. SOCS-3 binding to leptin receptors is believed to be a key event in the development of leptin resistance. Insulin receptors are similarly affected by SOCS-3, making it a candidate for the mediation of both insulin and leptin resistance. It is interesting and important to note that agents other than leptin, such as TNF-alpha, resistin, and FFA, also increase SOCS-3 activity.

Dr Flier continued by presenting information regarding 3 current research directions in his laboratory. He first discussed the role of FFA in insulin resistance. In particular, his laboratory is exploring how FFA are sensed by cells. The protein, toll-like receptor 4 (TLR4), may play a role. In support of this hypothesis, adipocytes from mice lacking TLR4 produce lower levels of the inflammatory cytokines, TNF-alpha and IL-6, in response to a high fat diet and lipids. In a second line of research, melanin concentrating hormone (MCH) has been identified as a regulator of energy balance that increases feeding. Antagonists of the MCH type 1 receptor (MCHR1) are being developed by as potential obesity treatments. Finally, Dr Flier’s lab is investigating the role of ciliary neurotrophic factor (CNTF) in neuronal plasticity that results in permanent changes in feeding behavior. Although CNTF was not effective in clinical trials for ALS, weight loss was reported as a side effect. Dr Flier’s lab has generated data indicating that part of CNTF’s effect on weight loss may be due to its ability to increase neurogenesis in the hypothalamus. These are new and exciting directions in obesity research, but they represent ongoing efforts, and the outcomes for clinical application cannot be predicted at this time. Dr Flier encouraged scientists in the audience to take similar risks in their research and pursue avenues whose destinations may not be so evident.