Cover Story Current Issue

Excessive lipid accumulation in adipose tissue triggers hypertrophy and stress of adipocytes, leading to infiltration of proinflammatory immune cells, fibrosis and adipocyte cell death, collectively referred to as adipose tissue dysfunction. As consequence, adipocytes capacity to store lipids is impaired and fat is ectopically accumulated in organs such as muscle, liver and pancreas, a condition that promotes organ dysfunction and insulin resistance, contributing to the pathogenesis of type 2 diabetes (T2D).

Although fat accumulation in human pancreas was described decades ago, it has for long remained an underexplored facet of ectopic fat distribution. Pancreatic fat has been associated with improved insulin secretion in normoglycaemic subjects, but with impaired insulin secretion in patients at increased risk of T2D. Furthermore, T2D diabetes remission, i.e. recovery of beta cell function was accompanied by reduction of pancreatic fat. These clinical observations point to the controversial role of pancreatic fat in insulin secretion, and emphasize the need for experimental evidence demonstrating plausible lipolysis derived fatty acids-/secretome-mediated effects of pancreatic adipocytes in islets. To date, detailed studies on the mechanistic interactions between pancreatic adipocytes and insulin secretion remain sparse, as reliable in vitro models replicating the unique properties of these cells have been lacking.

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Current Issue

Distinct genetic signals at the FGF21 locus complicate studies of FGF21's role in diet regulation using human cohort data

Stina Ramne, Mario García-Ureña, Matthew P. Gillum, Lars Ängquist, ... Niels Grarup

Distinct genetic signals at the FGF21 locus complicate studies of FGF21's role in diet regulation using human cohort data

 

Objectives

Experimental and genetic studies suggest that fibroblast growth factor 21 (FGF21) modulates macronutrient and alcohol preferences, but evidence of such regulation in humans remains scarce. To address this gap in translation, we aimed to map the relationships between plasma FGF21 levels, FGF21 genetic variation and habitual macronutrient intake in a large human population.

Methods

We fine-mapped and performed colocalization of the FGF21 genetic region in GWAS summary statistics of plasma FGF21 levels and macronutrient intake. UK Biobank data were used to investigate the associations between FGF21 genetic variants, plasma FGF21 protein levels, and macronutrient intake (including alcohol) assessed with repeated 24-hour recalls. One- and two-sample mendelian randomization were performed to estimate the effects of plasma FGF21 on macronutrient intake.

Results

We show that the main macronutrient-associated variant rs838133 and the FGF21 cis-pQTL rs838131, both in the FGF21 gene, are distinct genetic signals. Effect directions also suggest that the influence of FGF21 variation on macronutrient intake appear more complex than by direct mediation through plasma FGF21. Only when considering this complexity at FGF21, is plasma FGF21 estimated to reduce alcohol and increase protein and fat intake using mendelian randomization. Importantly, plasma FGF21 levels also appear markedly elevated by primarily high alcohol and low protein intake.

Conclusions

These findings support the feedback diet-regulatory mechanism of FGF21 in humans, but highlights the need for mechanistic characterization of the complex FGF21 genetic region.

 

 

Articles in Press

Distinct genetic signals at the FGF21 locus complicate studies of FGF21's role in diet regulation using human cohort data

Stina Ramne, Mario García-Ureña, Matthew P. Gillum, Lars Ängquist, ... Niels Grarup

Distinct genetic signals at the FGF21 locus complicate studies of FGF21's role in diet regulation using human cohort data

 

Objectives

Experimental and genetic studies suggest that fibroblast growth factor 21 (FGF21) modulates macronutrient and alcohol preferences, but evidence of such regulation in humans remains scarce. To address this gap in translation, we aimed to map the relationships between plasma FGF21 levels, FGF21 genetic variation and habitual macronutrient intake in a large human population.

Methods

We fine-mapped and performed colocalization of the FGF21 genetic region in GWAS summary statistics of plasma FGF21 levels and macronutrient intake. UK Biobank data were used to investigate the associations between FGF21 genetic variants, plasma FGF21 protein levels, and macronutrient intake (including alcohol) assessed with repeated 24-hour recalls. One- and two-sample mendelian randomization were performed to estimate the effects of plasma FGF21 on macronutrient intake.

Results

We show that the main macronutrient-associated variant rs838133 and the FGF21 cis-pQTL rs838131, both in the FGF21 gene, are distinct genetic signals. Effect directions also suggest that the influence of FGF21 variation on macronutrient intake appear more complex than by direct mediation through plasma FGF21. Only when considering this complexity at FGF21, is plasma FGF21 estimated to reduce alcohol and increase protein and fat intake using mendelian randomization. Importantly, plasma FGF21 levels also appear markedly elevated by primarily high alcohol and low protein intake.

Conclusions

These findings support the feedback diet-regulatory mechanism of FGF21 in humans, but highlights the need for mechanistic characterization of the complex FGF21 genetic region.

 

 

You are what you eat

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