Individual and combined effects of GIP and xenin on differentiation, glucose uptake and lipolysis in 3T3-L1 adipocytes

Abstract

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP), released postprandially from K-cells, has established actions on adipocytes and lipid metabolism. In addition, xenin, a related peptide hormone also secreted from K-cells after a meal, has postulated effects on energy regulation and lipid turnover. The current study has probed direct individual and combined effects of GIP and xenin on adipocyte function in 3T3-L1 adipocytes, using enzyme-resistant peptide analogues, (D-Ala2)GIP and xenin-25-Gln, and knockdown (KD) of receptors for both peptides. (D-Ala2)GIP stimulated adipocyte differentiation and lipid accumulation in 3T3-L1 adipocytes over 96h, with xenin-25-Gln evoking similar effects. Combined treatment significantly countered these individual adipogenic effects. Individual receptor KD impaired lipid accumulation and adipocyte differentiation, with combined receptor KD preventing differentiation. (D-Ala2)GIP and xenin-25-Gln increased glycerol release from 3T3-L1 adipocytes, but this lipolytic effect was significantly less apparent with combined treatment. Key adipogenic and lipolytic genes were upregulated by (D-Ala2)GIP or xenin-25-Gln, but not by dual peptide culture. Similarly, both (D-Ala2)GIP and xenin-25-Gln stimulated insulin-induced glucose uptake in 3T3-L1 adipocytes, but this effect was annulled by dual treatment. In conclusion, GIP and xenin possess direct, comparable, lipogenic and lipolytic actions in 3T3-L1 adipocytes. However, effects on lipid metabolism are significantly diminished by combined administration.

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“…However, activation of all three hormone signalling pathways appears to lead to reduced lipid deposition. In some agreement, interaction between xenin and GIP pathways within adipocytes has previously been noted to induce responses that contrast with effects of either hormone alone [ 46 ].…”

“…In agreement, whilst circulating lipid profile of HFF mice was improved by all treatment regimens, only combined therapy reduced triacylglycerol concentrations. In this regard, originally it was believed that xenin acts on adipose tissue to stimulate lipolysis [ 45 ], but more recent studies reveal direct lipogenic and adipocyte differentiation actions of xenin [ 46 ]. In agreement, an elegant study has suggested that neurotensin can also promote lipid accumulation [ 47 ].…”

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“… 32 There was an original hypothesis that xenin acts on adipose tissue to stimulate lipolysis, and that xenin may hold promise as an anti-obesity therapy by reducing adipose fat depots, but such observations were somewhat inconsistent. 32 Thus, English et al 33 recently revealed direct lipogenic and lipolytic actions of xenin in 3T3-L1 adipocytes, whilst also promoting adipocyte differentiation in 3T3-L1 pre-adipocytes, through alterations in gene expression of LPL and FASN, key promoters of 3T3-L1 differentiation. 33 The effects of xenin to positively modulate lipolysis, lipogenesis and adipocyte differentiation are likely modulated through NTRS1 activation on the AKT/PI3K pathway.…”

“… 32 Thus, English et al 33 recently revealed direct lipogenic and lipolytic actions of xenin in 3T3-L1 adipocytes, whilst also promoting adipocyte differentiation in 3T3-L1 pre-adipocytes, through alterations in gene expression of LPL and FASN, key promoters of 3T3-L1 differentiation. 33 The effects of xenin to positively modulate lipolysis, lipogenesis and adipocyte differentiation are likely modulated through NTRS1 activation on the AKT/PI3K pathway. 33 However, it should be noted that the actions of xenin on lipid metabolism are still not well defined and require more detailed study, especially in light of some conflicting observations.…”

“… 33 The effects of xenin to positively modulate lipolysis, lipogenesis and adipocyte differentiation are likely modulated through NTRS1 activation on the AKT/PI3K pathway. 33 However, it should be noted that the actions of xenin on lipid metabolism are still not well defined and require more detailed study, especially in light of some conflicting observations. 32 , 33 …”