METHOD FOR PROMOTING ADIPOCYTE DIFFERENTIATION AND OBESITY-RELATED DISEASE TREATMENT

• US 20200131238A1
• Filed: 10/24/2019
• Published: 04/30/2020
• Est. Priority Date: 10/25/2018
• Status: Active Grant

• Current Assignee: American University
• Original Assignee: American University
• Inventors: BRACHT, John R.
• Granted Patent: US 11,414,469 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/473 alpha-Glycoproteins
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C12N 2501/11 Epidermal growth factor [EGF]
• CPC Class Codes: C12N 2501/13 Nerve growth factor [NGF]; Brain-derived neurotrophic factor [BDNF]; Cilliary neurotrophic factor [CNTF]; Glial-derived neurotrophic factor [GDNF]; Neurotrophins [NT]; Neuregulins
• CPC Class Codes: C12N 2506/1384 from adipose-derived stem cells [ADSC], from adipose stromal stem cells
• CPC Class Codes: C12N 5/0653 Adipocytes; Adipose tissue

Abstract

Here we show that epigenetic control of Neuregulin-1 (NRG1) affects adipose differentiation of stem cells in vitro. Building on this finding, we established a model in which NRG1 is a white adipose tissue (WAT) specific regulator analogous to the role of NRG4 in black adipose tissue (BAT). In this light, NRG1 functions in a paracrine or autocrine manner to regulate formation of new adipocytes from stem populations, both in vitro and in vivo. In neurons, NRG1 has been shown already to play a similar role, promoting neuronal cell differentiation from progenitors in the vertebrate cortex and retina and even promoting neuronal differentiation in vitro. Similarly, in the heart, NRG1 promotes differentiation of cardiomyocytes from their stem cell progenitors both in vivo and in vitro and for this reason has been successfully tested in clinical trials for heart failure. Our model extends these findings to adipose biology and indicates that epigenetic control of NRG1 may constitute an intrinsic mechanism limiting the expansion of WAT depots, potentially elucidating important health implications for the comorbidities of obesity and providing treatment for obesity-related diseases.

Claims

1. A method for increasing the differentiation of preadipocytes into adipocytes, the method comprising exposing the preadipocytes to Neuregulin-1 under conditions sufficient to promote differentiation of the preadipocytes into adipocytes.

2. The method of claim 1, wherein the Neuregulin-1 is NRG1 β

.

3. The method of claim 1, wherein the Neuregulin-1 is the Type III isoform of NRG1.

4. The method of claim 1, wherein the Neuregulin-1 is a fragment of NRG1 β

comprising an EGF-binding domain.

5. The method of claim 4, wherein the fragment of NRG1 β

is SEQ ID NO;

1.

6. The method of claim 1, wherein the Neuregulin-1 is provided at a concentration of about 1 ng/ml to about 500 ng/ml.

7. The method of claim 1, wherein the preadipocytes are white adipose tissue (WAT) preadipocytes.

8. The method of claim 1, wherein the method is performed in vitro or in vivo.

9. The method of claim 8, wherein when the method is performed in vivo, the increase in the differentiation of the preadipocytes into adipocytes results in an increase in the number of adipocytes.

10. The method of claim 8, wherein when the method is performed in vivo, exposing the preadipocytes to Neuregulin-1 results in at least one of the following:

increased leptin levels, lowered inflammation, decreased blood sugar, increased insulin sensitivity, lowered insulin levels, decreased hypertension, resolution of hyperlipidemia, lowered bodyweight.

11. A method for increasing the differentiation of adipose-derived stem cells (ASCs) into adipocytes, the method comprising exposing the ASCs to Neuregulin-1 under conditions sufficient to promote differentiation of the ASCs into adipocytes.

12. The method of claim 11, wherein the Neuregulin-1 is NRG1 β

.

13. The method of claim 11, wherein the Neuregulin-1 is the Type III isoform of NRG1.

14. The method of claim 11, wherein the Neuregulin-1 is a fragment of NRG1 β

comprising an EGF-binding domain.

15. The method of claim 14, wherein the fragment of NRG1 β

is SEQ ID NO;

1.

16. The method of claim 11, wherein the Neuregulin-1 is provided at a concentration of about 1 ng/ml to about 500 ng/ml.

17. The method of claim 11, wherein the ASCs are white adipose tissue (WAT) ASCs.

18. The method of claim 11, wherein the method is performed in vitro or in vivo.

19. The method of claim 18, wherein when the method is performed in vivo, the increase in the differentiation of the ASCs into adipocytes results in an increase in the number of adipocytes.

20. The method of claim 18, wherein when the method is performed in vivo, exposing the ASCs to Neuregulin-1 results in at least one of the following:

increased leptin levels, lowered inflammation, decreased blood sugar, increased insulin sensitivity, lowered insulin levels, decreased hypertension, resolution of hyperlipidemia, lowered bodyweight.