Can We Suppress Sugar Cravings?

FGF21 is a fibroblast growth factor (FGF) and hormone-like protein researched by Anthony Kliewer, PhD, at the University of Texas at Dallas, for its ability to regulate metabolism. It is a member of atypical FGFs and is expressed in the liver, pancreas, and adipose tissue, but only secreted from the liver under normal physiological conditions. It is regulated in response to a variety of metabolic stresses. This protein has been under investigation for at least 12 years, when it was seen that pharmacologic administration of FGF21 caused profound weight loss and markedly improved insulin sensitivity in primates.^1-2 Further, in previous clinical trials, FGF21 analogs have shown weight loss and improved lipid levels in obese patients with type 2 diabetes.^3-4

Dr. Kliewer undertook research to discover the specific physiological pathways of this molecule. He and his colleagues studied not only FGF21 but also a second protein that was found to be “absolutely essential” for FGF21 to act: βKlotho. This protein forms a complex with the FGF21 bar and sits on the surface of cells found only in adipose tissue and the central nervous system (CNS). Their research used selectively cross-bred mice to generate adipose tissue specific to βKlotho and found that it a had a marked effect on glucose uptake, expressly in brown adipose tissue. With this result, his team became interested in determining the long-term effects on body weight and insulin sensitivity. They found a striking effect of a 15-20% decrease in body weight, independent of its acting effects on the tissues.

Referencing prior work done by Angie Bookout, who mapped the location of βKlotho throughout the body, they knew that it was expressed specifically in the hypothalamus and hindbrain, and that it does cross the blood brain barrier. They found that the action on the CNS was facilitated by a sympathetic outflow to brown adipose tissue: not by a suppression of food intake, but rather by increased thermogenesis and subsequent increased energy expenditure. FGF21 and βKlotho also acted directly on brown adipose tissue to normalize insulin levels. According to Dr. Kliewer, “this uptake of fuel into adipose tissue drives the fire to burn that fuel.”   

Their research further discovered that FGF21, again by acting on the CNS, was able to reduce sweet preference in mice, almost to the point of revulsion at 2 weeks into the trial. When the trial was replicated in primates, they found a suppression of saccharin intake within one day. However, they also found a washout period where the effects did reverse.

When approached by a group of researchers from the United Kingdom (Schumann, Elliott, Mϋller), Dr. Kliewer’s team investigated the link between βKlotho and alcohol consumption, finding that while FGF21 is induced by alcohol and associated with decreased social drinking, it was unknown whether alcohol consumption affected βKlotho levels. Their hypothesis was that this pathway may be important for alcohol preference as their trial mice showed a marked decrease in ethanol consumption. Their early stages of research looked at neurotransmitter levels and utilized the lab at Vanderbilt for brain analysis. The team found that dopamine levels were suppressed by the release of FGF21 into the circulation by the liver in response to both sugar and alcohol in the bloodstream. They speculated that this pathway evolved as protection from over-consumption as it stimulates a whole-body glucose uptake in order to assist in the regulation of carbohydrate homeostasis.

Dr. Kliewer acknowledged investigation by other groups that have corroborated this pathway with additional published papers. He particularly noted research from the University of Iowa.

As for the utility potential of FGF21 as a drug with which to combat obesity, Dr. Kliewer stated that there were both pros and cons. Its advantages include significant weight loss, improved insulin sensitivity, improved lipid profile, life span extension, and sweet/alcohol preference reduction. Because of its expected stimulation of sympathetic nerve activity, however, long-term effects of increased blood pressure, bone loss, and depression were noted. In Dr. Kliewer’s words, “As a drug, it’s interesting and challenging, but there certainly are a number of challenges to overcome for this to be developed.”

Session S09: Where is the Sweet Tooth? Mechanisms Governing Palatable Intake and Weight Gain. ENDO 2017 annual meeting, Orlando, FL. April 1, 2017

References:

1. Kharitonenkov A, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005 Jun;115(6):1627-1635.

2. Kharitonenkov A, et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology. 2007 Feb;148(2):774-781.

3. Gaich G, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013 Sep 3;18(3):333-340.

4. Talukdar S, et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 2016 Mar 8;23(3):427-440.