TGF-b Superfamily Cytokine MIC-1/GDF15 Is a Physiological Appetite and Body Weight Regulator

Abstract

The TGF-b superfamily cytokine MIC-1/GDF15 circulates in all humans and when overproduced in cancer leads to anorexia/cachexia, by direct action on brain feeding centres. In these studies we have examined the role of physiologically relevant levels of MIC-1/GDF15 in the regulation of appetite, body weight and basal metabolic rate. MIC-1/GDF15 gene knockout mice (MIC-1−/−) weighed more and had increased adiposity, which was associated with increased spontaneous food intake. Female MIC-1−/− mice exhibited some additional alterations in reduced basal energy expenditure and physical activity, possibly owing to the associated decrease in total lean mass. Further, infusion of human recombinant MIC-1/GDF15 sufficient to raise serum levels in MIC-1−/− mice to within the normal human range reduced body weight and food intake. Taken together, our findings suggest that MIC-1/GDF15 is involved in the physiological regulation of appetite and energy storage.

Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity

“…Among the 167 genes that were upregulated more than 2-fold, 24 genes were found to contain a signal peptide. At the top of this list, there were 6 secreted proteins that have been linked to energy expenditure, including FGF21 (26), BMP8b (29), GDF15 (50,51), angiopoietin-like 6 (ANGPTL6) (52), neuromedin B (NMB) (53), and nesfatin (NUCB2) (54), and verified by qPCR (Fig. 6A).…”

Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals

“…While the hyperphagia in Bscl2 Ϫ / Ϫ mice can be attributed to leptin defi ciency caused by an absence of adipose tissue, the lower plasma level of leptin in Ad-mKO mice suggests a leptin-independent mechanism for reduced food intake in Ad-mKO mice. One potential explanation is upregulated expression of Gdf15, a newly-identifi ed anorexigenic adipokine ( 64 ). While the mRNA expression of Gdf15 was signifi cantly increased in Ad-mKO mice (supplementary Table 1), whether circulating Gdf15 levels are suffi cient to negatively regulate food intake remains to be .…”

Weight Loss Correlates with Macrophage Inhibitory Cytokine-1 Expression and Might Influence Outcome in Patients with Advanced Esophageal Squamous Cell Carcinoma

“…Our study did demonstrate that MIC-1 concentration was closely related to weight loss before chemotherapy, which indicated that MIC-1 may cause weight loss by decreasing appetite in ESCC patients. Some studies had also indicated that serum MIC-1 was closely associated with energy intake and expenditure and systemic inflammation (Skipworth RJ et al, 2010;Tsai VW et al, 2013). Our study concerning those fields is ongoing.…”

“…However, there have been no studies on advanced ESCC patients that examined the mechanisms underlying appetite loss. MIC-1 (Johnen et al, 2007;Macia et al, 2012;Tsai et al, 2013) could act on TGF-β RII receptors in hypothalamic neurons, and then reduce neuropeptide Y expression and increase pro-opiomelanocortin expression, which may decrease appetite. MIC-1 is overproduced in many types of cancers (Welsh et al, 2003;Bauskin et al, 2006).…”

“…Macrophage inhibitory cytokine-1 (MIC-1) is a transforming growth factor-β (TGF-β) superfamily protein (Bootcov et al, 1997). It is involved in the physiological regulation of appetite and energy storage (Tsai et al, 2013) with a normal range of 150-1,150 pg/ml in the circulation of individuals (Brown et al, 2002a;Brown et al, 2002b). Its expression level may be induced by inflammation, injury and malignancy (Breit et al, 2011) and high concentration of MIC-1 has been observed in many types of cancers (Welsh et al, 2003;Bauskin et al, 2006;Lu ZH et al, 2014).…”