Susan Weimer, DPT, PT

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.

 Further, in previous clinical trials, FGF21 analogs have shown weight loss and improved lipid levels in obese patients with type 2 diabetes.

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: Î²Klotho. 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 Î²Klotho 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 Î²Klotho 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 Î²Klotho 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, MÏller), Dr. Kliewer’s team investigated the link between Î²Klotho and alcohol consumption, finding that while FGF21 is induced by alcohol and associated with decreased social drinking, it was unknown whether alcohol consumption affected Î²Klotho 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. 

 annual meeting, Orlando, FL. April 1, 2017

. J Clin Invest. 2005 Jun;115(6):1627-1635.

The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21

. Endocrinology. 2007 Feb;148(2):774-781.

The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes

A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects

Articles

Researchers sought to discover the specific physiological pathways of fibroblast growth factor 21.

Can We Suppress Sugar Cravings?

Jens Ãllgaard, the primary researcher from his team based out of Denmark, presented on their research entitled: Increased Survival and Reduced Macrovascular Disease with 7.8 Years of Intensified, Multifactorial Intervention in Patients with Type 2 Diabetes and Microalbuminuria in the Steno-2 Study.

Their research encompassed 21 years of follow up in a cohort of 160 patients with type 2 diabetes and microalbuminuria. The patients were assigned to conventional or intensified, multi-factorial therapy targeting multiple risk factors. Mean treatment duration was 7.8 years, at which time the study continued as an observational follow-up with all patients treated as the original intensive-therapy group.

The primary endpoint was survival time after randomization and survival time before the first cardiovascular disease (CVD) event. The secondary endpoint was the relative risk reduction in a 3-point MACE defined as: death from CVD, coronary artery disease, and cerebrovascular disease (defined as non-fatal and fatal ischemic or hemorrhagic stroke).

Their results showed both a reduction in CVD death by 60% and an increased survival rate of 7.9 years in the intensified treatment group. There was substantial and stable risk reduction in all endpoints. In response to a question following his presentation, Dr. Ãllgaard further theorized that “the reduction in cardiovascular disease and risk of stroke could possibly minimize associated dementia” as well.

In summary, he felt that their work strongly supported the importance of early intervention in persons with type 2 diabetes.

Also in this session, Andrea Kelly, MD, MSCE, from the University of Pennsylvania, presented on research entitled: New Criteria for Indeterminate Glucose Tolerance in Pancreatic Insufficient Cystic Fibrosis Based on Defects in Î²-Cell Secretory Capacity.

Dr. Kelly reported that estimates point out that 40-50% of adults will develop type 2 diabetes; this is clinically relevant to the cystic fibrosis (CF) population as diabetes would constitute a second chronic disease to the already-debilitating disease of CF. The combination of CF and diabetes is associated with not only microvascular disease, but also worsening of nutritional status, deterioration of pulmonary function, and increase in mortality. Early recognition and treatment of the diabetes risk can help mitigate the increased mortality risk.

Insulin insufficiency largely accounts for the development of CF diabetes but the mechanisms have not been fully understood. According to Dr. Kelly, the decrease in Î²-cell mass does not always identify which patients will develop diabetes. To better identify those patients with early defects in insulin secretion, she and her colleagues sought evidence of impaired Î²-cell secretory capacity (a measure of functional Î²-cell mass) by using a more stringent parameter for characterizing indeterminate glucose tolerance. They speculated that this might be the earliest clinical sign of insulin secretion abnormalities. Their parameter was a 1-hour plasma glucose of ≥155mg/dL as this had been shown to detect early signs of cardiovascular disease associated with type 2 diabetes risk. Metabolic tests were conducted across groups of patients with pancreatic insufficient cystic fibrosis (PI) categorized by an oral glucose tolerance test (OGTT) as normal, indeterminate, impaired, and diabetic.

Dr. Kelly and her colleagues concluded that PI patients with a 1-hour OGTT glucose as low as 155mg/Dl can already be identified with early impairments in Î²-cell secretory capacity and that this capacity is further taxed by increased insulin secretory demand. She suggested that further studies could address whether dietary and/or pharmacological interventions to reduce pancreatic Î²-cell stress in PI patients may delay the progression to the development of CF diabetes.

Session OR11: Clinical Dilemmas and Outcomes in Diabetes. 

Research presented at ENDO 2017 explored options to reduce complications in patients with diabetes and microalbuminuria and patients with cystic fibrosis.

Clinical Dilemmas in Diabetes

Research performed at the University of Michigan is helping to determine how cue-triggered motivational responses differ both before and after the onset of obesity, and how these responses can be linked to a difference in striatal function between obese and non-obese populations.

According to lead investigator Carrie Ferrario, PhD, “Obesity is a very complicated problem, and it has very different contributing factors.” Various stimuli are believed to influence our eating behaviors and can encourage us to eat larger portions, as well as encourage us to make food choices that we ordinarily might not. Obese people tend to be more sensitive to the motivational properties of food. The University of Michigan researchers hypothesized that enhanced cue-trigger urges might contribute to overall food consumption and drive the development of obesity.

The integration of dopamine and glutamate is essential in activating the striatum, and the magnitude of this response, stronger in the obese, can predict future weight gain and poor weight loss outcomes. Dr Ferrario feels that the evidence suggests that there are differences in the function of the striatum both before and after the development of obesity.

She and her colleagues completed their study on two groups of rats selectively bred for both obesity and resistance to obesity. This research focused on changes in the nucleus accumbens (NAc), an area of the brain increasingly being associated with obesity. The calcium permeable AMPA receptors (CP-AMPARs) in this region are critical to responses for motivation and reward. Her research helped corroborate a previous finding that eating highly palatable, junk-type foods enhances excitatory transmission in the NAc and is mediated by the AMPA receptors; blocking the transmission of the AMPA receptors prevented the cue-triggered food-seeking behaviors by the obese animals but had only a weak effect on this behavior in the obesity-resistant group. She specifically observed a 30% up-regulation of AMPA receptors in the obesity-prone group in response to eating palatable foods. Moreover, these increases occurred prior to the diagnosis of obesity.

Her conclusions validated previous research in this area (Robinson, et al. Neuropsychopharmacology 2015), showing that up-regulation contributes to behavior and occurs more readily in obesity-prone rats, driving over-consumption.

Conversely, blocking the CP-AMPARs was sufficient to block the behavior in these animals. Dr. Ferrario concluded, “cue-triggered food-seeking is stronger in obesity- prone rats as compared to obesity-resistant rats and this is happening before any overt dysregulation.” She further expounded, “experience with things like junk food and PIT training are sufficient to increase CP-AMPARs in the NAc.”

In summary, the research data of Dr Ferrario and her colleagues supports the idea of basal differences in cue-triggered motivation and suggests that cue-triggered motivational responses may contribute to the development of obesity in susceptible individuals. Striatal function differs in obese versus non-obese individuals and shows a plasticity from before and after the development of obesity. Further research investigating these neural mechanisms and plasticity can be used to direct treatment development.

Individual Differences in Cue-Induced Motivation and Striatal Systems in Rats Susceptible to Diet-Induced Obesity

. Neuropsychopharmacology. 2015 Aug;40(9):2113-2123.

Researchers investigated possible differences in the function of the striatum both before and after the development of obesity.

Susan Weimer, DPT, PT

Articles

Can We Suppress Sugar Cravings?

Clinical Dilemmas in Diabetes

Role of the Striatum in Obesity