Keeping Warm In The Cold Human Brown Adipose Tissue Upon Cold

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( -.!/01!( 23%$"43*(.5$%%$3*(135364#78+9:357;"<=(135364#78+,!W%&01*&ST)&/#$7*+M&X&9>& 01*&FF&<$,0/8/<$%0+&+19.*-&$&<,9%9"%8*-&EOY&"<0$Z*&/%&'()=&E9,&[&<$,0/8/<$%0+M& 01*& EOY& "<0$Z*& .$+& %*7:/7/C:*M& $%-& 01*+*& <$,0/8/<$%0+& -/-& %90& 1$?*& 89##9%& 81$,$80*,/+0/8+=&(&0D&EOY&"<0$Z*&/+&+19.%&/%&E/7",*+&H'&$%-&N=& \<0$Z*& /%& 01*& +"<,$8:$?/8":$,M& 8*,?/8$:M& $%-& <$,$+?@(%/(=?@(AB3:C(DEFC( ! A 18F-FDG injection 45 min 4-17 min 30 min Start PET imaging C 60 min B ce sc ps D E >J ! 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'&53&<%/0.( 4/%2<"20:'/#3($'2%20(3&#NB(=#,(,/4/3#'(G&52'&!#0:(#5%&'(<23:(#<<3/4#%/20(IDJ)9P(U( DD9J(1,9(DQ*9*(U(DD9*($423V!I,W4.KVIM%X>7(<2$@(0-4G&',K(Y(DR9RRRB('&,$&<%/1&3@A( Z/.-'&( J6K9! S0( #::/%/20B( #3,2( %"&( 4#C/4#33@( <2-$3&:( I,%#%&( QK( #0:( 4#C/4#33@! -0<2-$3&:( I,%#%&( [B( '&53&<%/0.( %"&( <#$#6&#)(*&*-?%0*()/#&*-$%#-&@%5-06(5&*("+%(+% AB%)(*"',"+$5(&!(+%&%$"0-C$-6-+$-+*%)&++-5%>$&*&%+"*%0,"D+?;%% % 3000 2000 1000 D! 20 10 0 PRE POST M MO MG F! State U permeabilized muscle fibers 500 400 300 200 100 0 PRE POST H! EC50 (nM free palmitate) 200 150 100 50 0 PRE POST State 3 Isolated Mitochondria J! 5000 4000 3000 2000 PRE 1000 POST 0 Pyruvate Palmitoyl-CoA pmol O2/s/mg mitochondrial protein 30 250 pmol O2/s/mg mitochondrial protein pmol/(s*mg)/ (MtDNA copy numbers x 10.000) State 2 Permeabilized muscle fibers Vmax (pmol O2/s/mg mitochondrial protein) pmol/(s*mg)/ (MtDNA copy numbers x 10.000) pmol/(s*mg)/ (MtDNA copy numbers x 10.000) POST 40 E! G! PRE pmol O2/s/mg mitochondrial protein 0 C! I! pmol/(s*mg)/ (MtDNA copy numbers x 10.000) B! 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%'#-.?&''&2( %4( -B3&'0/( 2#%#( 5?'43( 7H;7( ?4'( .&-.#%04-8( ?'43(H=J;(%4(H7J;(#-2(7J;(%4(=J;(?4'(/43?4'%(#-2(7H;7(?4'(."0D&'0-@>8(.4(%"#%(#-#AK.&.( /4BA2(1&(24-&J(S-/'&3&-%#A(#'&#(B-2&'(%"&(/B'D&(L#.(/#A/BA#%&2(?4'(2#K(=(5+("4B'.>( #-2( 2#K( ;7( 5+( "4B'.>( #-2( %"&.&( D#AB&.( L&'&( /43$#'&2( 1K( 3&#-.( 4?( #( $#0'&2( .#3$A&(%(%&.%J(( ( How are you feeling now? Cold Cool Slightly Cool Neutral Slightly Warm Warm Hot Do you think this is…? Very Comfortable Comfortable Just Comfortable Just Uncomfortable Uncomfortable Very Uncomfortable Do you shiver? Yes Sometimes Tense muscles No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