Title: In situ hybridization of a human TYR RNA probe on sections of visceral adipose tissues from morbidly obese and non-obese subjects demonstrated cytoplasmic and membrane-associated staining pattern (20x magnification). A and B. T7 (cTYR) probe, morbidly
1In situ hybridization of a human TYR RNA probe on
sections of visceral adipose tissues from
morbidly obese and non-obese subjects
demonstrated cytoplasmic and membrane-associated
staining pattern (20x magnification). A and B.
T7 (cTYR) probe, morbidly obese subject. C. T7
(cTYR) probe, lean subject. D. SP6 (control)
probe, visceral adipose tissue from a morbidly
obese subject.
2Figure 6. Immunohistochemical staining of
visceral adipose tissue with TYR, TYRP1 and
TYRP2 Ab A, C, E, G morbidly obese subject.
B, D, F, H non-obese subject. A and B
Tyrosinase C and D Tyrosinase-related protein
Tyrp2 (dopachrome tautomerase) E and F
Tyrosinase-related protein Tyrp1 G and H
Negative control (secondary antibodies) and
DAPI.
3Relative abundance of MC1R, TYR, TYRP1 and TYRP2
transcripts in adipose samples from obese and
lean subjects
4Results of the L-U-14C tyrosine assay that
measures the total outputs of melanogenic pathway
in tissue extracts.
5Whymelanin is present in adipose? What
regulates its biosynthesis?
Most important questions
A.
6Melanocyte-stimulating hormone (a-MSH)
- Stimulates the production and release of melanin
by melanocytes in skin and hair. - Anorexigenic peptide (suppresses appetitis,
decrease body weight and food intake) - a-MSH signaling interplays with sensitivity to
insulin
7DIFFERENTIATING ADIPOCYTES ARE RESPONSIVE to
a-MSH
2 hours
6 hours
24 hours
0 hours
2 hours
6 hours
24 hours
0 hours
8a-MSH in human subjects
Plasma a-MSH, pmol/l Plasma AGRP, pg/ml
Lean Humans (N11) 15.8 /- 1.2 5.8 /- 1.0
Obese humans (N18) 49.4 /- 2.4 10.1 /- 0.9
Significant? P lt 0.001 P lt 0.001
a-MSH correlates closely with fat mass (P lt
0.001), percentage body fat (P lt 0.001) and
leptin (P lt 0.05).
Hoggard N. et al., Clin Endocrinol (Oxf). 2004
Jul61(1)31-9.
9This is an indication of central a-MSH
resistance in human obesity
- So,
- obese adipocytes are exposed to increased amount
of - a-MSH
10Is it good for adipocyte to produce melanin?
- Melanin is a strong anti-inflammatory agent (when
injected in mice) suppesses ILs and TNF-a
production - 2) Melanin prevents oxidative damage inside the
cells, serving as the molecular dump for free
radicals - 3) Obese adipocytes are under heavy oxidative
stress (beta-oxidation produces tons of radicals)
11Hypothesis
- It is beneficial for obese adipocytes
- to produce melanin, as it prevents cell death
under oxidative duress. - Side effects
- - Suppression of the production of inflammatory
substances by adipose - Suppression of systemic inflammation of obesity
- Suppression of IR
- Supression of secondary complications of obesity
(metabolic syndrome, NAFLD, CVD)
12Collateral hypothesis
- Melanin biosynthesis system is extremely
polymorphic in humans - Variation in melanogenesis in adipose may reflect
- variation of predisposition
- to the development of secondary disorders
- in obese persons.
13Therapeutic idea
- Lets stimulate melanogenesis in adipose
- to prevent NAFLD and CVD in obesity and
- metabolic syndrome
Two synthetic analogs of a-MSH, based upon a
cyclical peptide called Melanotan II are being
developed for human use, one by an Australian
company, the other by Palatin Thechnologies (NJ)
Bremelanotide (formerly PT-141) is tested for
therapeutic tanning and sexual dysfunction
14May be the war against obesity is futile. It goes
for so long already, without much success.
Stimulation of melanin biosynthesis in obese
individuals may turn off proinflammatory
function of adipose, Decrease morbidity in obese
individuals, Cut economic losses in society
Remove some stigma from obesity
15Acknowledgement
16METABOLIC SYNDROME RELATED STUDIES
- GMU Team
- Mohammed Jarrar (PhD Student) now PhD
- Manpreet Randhawa (PhD Student) now PhD
- Tom Huff (melanin specs)
- Dr. Vikas Chandhoke
- (who initiated GMU-INOVA collaboration)
17METABOLIC SYNDROME RELATED STUDIES
- INOVA Team
- Dr. Zobair Younossi (Clinical Team leader)
- Maria Stepanova - statistician
- A Team of Surgeons and Hepatologists who
provided - well characterized samples for the study
- Immunostainings of the adipose tissue for
melanin studies were performed in the lab of - Prof. Vincent Hearing (NIH, NCI)
Study of the melanin in the adipose was supported
by Jeffress Foundation