Leon G. Straub

FGF21, energy expenditure and weight loss - How much brown fat do you need?

Background Fibroblast growth factor 21 (FGF21) belongs to the large family of fibroblast growth factors (FGFs). Even though FGF signaling has been mainly implicated in developmental processes, recent studies have demonstrated that FGF21 is an important regulator of whole body energy expenditure and metabolism, in obesity. Scope of review Given the fact that obesity has developed epidemic proportions, not just in industrialized countries, FGF21 has emerged as a novel therapeutic avenue to treat obesity as well as associated metabolic disorders. While the metabolic effects of FGF21 are undisputed, the mechanisms by which FGF21 regulate weight loss have not yet been fully resolved. Until recently it was believed that FGF21 induces brown fat activity, thereby enhancing energy expenditure, which concomitantly leads to weight loss. Novel studies have challenged this concept as they could demonstrate that a part of the FGF21 mediated effects are retained in a mouse model of impaired brown adipose tissue function. Major conclusions The review illustrates the recent advances in FGF21 research and discusses the role of FGF21 in the regulation of energy expenditure linked to brown fat activity.

Regulation of De Novo Adipocyte Differentiation Through Cross Talk Between Adipocytes and Preadipocytes

There are many known adipokines differentially secreted from the different adipose depots; however, their paracrine and autocrine effects on de novo adipocyte formation are not fully understood. By developing a coculture method of preadipocytes with primary subcutaneous and visceral adipocytes or tissue explants, we could show that the total secretome inhibited preadipocyte differentiation. Using a proteomics approach with fractionated secretome samples, we were able to identify a spectrum of factors that either positively or negatively affected adipocyte formation. Among the secreted factors, Slc27a1, Vim, Cp, and Ecm1 promoted adipocyte differentiation, whereas Got2, Cpq, interleukin-1 receptor-like 1/ST2-IL-33, Sparc, and Lgals3bp decreased adipocyte differentiation. In human subcutaneous adipocytes of lean subjects, obese subjects, and obese subjects with type 2 diabetes, Vim and Slc27a1 expression was negatively correlated with adipocyte size and BMI and positively correlated with insulin sensitivity, while Sparc and Got2 showed the opposite trend. Furthermore, we demonstrate that Slc27a1 was increased upon weight loss in morbidly obese patients, while Sparc expression was reduced. Taken together, our findings identify adipokines that regulate adipocyte differentiation through positive or negative paracrine and autocrine feedback loop mechanisms, which could potentially affect whole-body energy metabolism.

LSD1 Makes Fat Colorful

The histone lysine-specific demethylase 1 (LSD1) is a new and important player in the regulation of brown fat identity and function. In a recent Cell Reports article, Duteil et al. show that LSD1 exerts its effects via regulation of specific histone marks as well as through association with co-repressor complexes.

Short‐term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high‐fat diet

A ketogenic diet is known to lead to weight loss and is considered metabolically healthy; however there are conflicting reports on its effect on hepatic insulin sensitivity. KD fed animals appear metabolically healthy in the fasted state after 3 days of dietary challenge, whereas obesogenic high‐fat diet (HFD) fed animals show elevated insulin levels. A glucose challenge reveals that both KD and HFD fed animals are glucose intolerant. Glucose intolerance correlates with increased lipid oxidation and lower respiratory exchange ratio (RER); however, all animals respond to glucose injection with an increase in RER. Hyperinsulinaemic–euglycaemic clamps with double tracer show that the effect of KD is a result of hepatic insulin resistance and increased glucose output but not impaired glucose clearance or tissue glucose uptake in other tissues.

Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring

Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.How heavy a person is and how much active brown fat they have depends on their father and the season in which they were conceived.

Lessons from Cre-Mice and Indicator Mice

The adult human adipose tissue is predominantly composed of white adipocytes. However, within certain depots, adipose tissue contains thermogenically active brown-like adipocytes, which have been evolutionarily conserved in mammals. This chapter will give a brief overview on the methods used to genetically target and trace both white and brown adipocytes using techniques such as bacterial artificial chromosome (BAC) cloning to create transgenic mouse models and the tools with which genetic recombination is mediated in vivo (e.g., Cre-loxP, CreERT, and Tet-On). The chapter furthermore critically discusses the strength and limitation of the various systems used to target mature white and brown adipocytes (ap2-Cre, Adipoq-Cre, and Ucp1-Cre). Based on these systems, it is evident that our knowledge of mature adipocyte categorization into brown, white, brite, or beige adipocytes is strongly influenced by the use of the various genetic mouse models described in this chapter. Our evaluation of different studies using the aforementioned systems focuses on key genes, which have been reported to maintain adipocytes function (insulin receptor, Raptor, or Atgl).

Author Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring

In the version of this article originally published, the months on the axis labeled projected month of conception in Fig. 1a were out of order. April and March should have been the first and last months listed, respectively. The error has been corrected in the print, PDF and HTML versions of this article.

Publisher Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring

In the version of this article originally published, the bars in the mean temperature graph in Fig. 1a were incorrectly aligned. The left-most bar should have been aligned with the Apr label on the projected month of conception axis. The error has been corrected in the print, PDF and HTML versions of this article.