JOURNAL ARTICLE

Mapping of biguanide transporters in human fat cells and their impact on lipolysis

Peter Arner, Agné Kulyté, Kenneth Batchelor, Jurga Laurencikiene, James Livingston, Mikael Rydén
Diabetes, Obesity & Metabolism 2018, 20 (10): 2416-2425
29862627

AIM: To examine the cell membrane transporters involved in mediating the antilipolytic effect of biguanides in human fat cells.

MATERIALS AND METHODS: Gene expression of biguanide transporters was mapped in human subcutaneous adipose tissue and in adipocytes before and after differentiation. Those expressed in mature fat cells were knocked down by RNA interference (RNAi) and the antilipolytic effects of metformin and two novel, highly potent biguanides, NT1014 and NT1044, were examined.

RESULTS: Analysis of the transporter affinity of biguanides in HEK293 cells overexpressing individual transporters showed that NT1014 and NT1044 had >10 times higher affinity than metformin. Animal studies showed that NT1014 was >5 times more potent than metformin in lowering plasma glucose in mice. In human fat cells, the novel biguanides displayed higher AMP-activated protein kinase activation and antilipolytic efficacy than metformin. Five transporters, organic cation transporter (OCT)1 (SLC22A1), organic cation transporter novel type 1 (OCTN1; SLC22A4), OCT3 (SLC22A3), plasma membrane monoamine transporter (PMAT; SLC29A4) and multidrug and toxin extrusion transporter (MATE1; SLC47A1), were detectable in fat cells but only OCT3, PMAT and MATE1 increased during adipogenesis in vitro and were enriched in fat cells compared with other adipose cell types. Gene knockdown by RNAi showed that MATE1 and PMAT reduction attenuated the antilipolytic effect of metformin but only PMAT knockdown decreased the effect of all three biguanides.

CONCLUSIONS: While human fat cells primarily express three biguanide transporters, our data suggest that PMAT is the primary target for development of fat cell-specific antilipolytic biguanides with high sensitivity and potency.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
29862627
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"