Irving 2012 Abstract IOC72: Difference between revisions

Latest revision as of 17:32, 7 November 2016

Irving BA (2012) AgRP deficient female mice have elevated body weight and hypothalamic mitochondrial oxidative capacity. Mitochondr Physiol Network 17.13.

Link: IOC72 Open Access

Irving BA (2012)

Event: IOC72

The central orexigenic agouti-related protein (AgRP) increases food intake when ubiquitously over expressed. Unexpectedly, AgRP deficiency also produces elevated food intake in female, but not male AgRP (-/-) mice. Moreover, the female AgRP (-/-) tend to be heavier than their wild type (WT) littermates. We therefore examined whether differences in mitochondrial respiratory capacity and control could contribute to the propensity of the female AgRP (-/-) mice to eat more and gain more weight compared to their WT littermates. High-resolution respirometry was utilized to perform multiple substrate-inhibitor titration (SUIT) protocols designed to assess mitochondrial respiratory capacity and control in (mechanically and/or chemically) permeabilized hypothalamus, liver, skeletal muscle, and white adipose tissue acquired from female AgRP (-/-) and their WT littermates. In the hypothalamus, the female AgRP (-/-) mice had higher state-3 respiration (glutamate+malate+succinate+ADP) and higher maximally uncoupled respiration (FCCP) than their WT littermates. However, there were no significant differences between groups for the respiratory control ratios in the hypothalamus. Likewise, there were no significant differences between groups for the O2 fluxes or respiratory control ratios in the liver, white adipose tissue, or gastrocnemius muscle. Similar to the present results, obese Zucker rats were reported to have enhanced mitochondrial oxidative capacity in the hypothalamus (1). In conclusion, AgRP deficiency in female mice results in elevations in hypothalamic mitochondrial oxidative capacity, likely contributing to their increased food intake and body weight.

[1] Colombani AL, Carneiro L, Benani A, Galinier A, Jaillard T, Duparc T, Offer G, Lorsignol A, Magnan C, Casteilla L, Penicaud L, Leloup C (2009) Enhanced hypothalamic glucose sensing in obesity: alteration of redox signaling. Diabetes 58: 2189-2197 Open Access

• Keywords: Orexins, Agouti-related protein, Obesity

• O2k-Network Lab: US MN Rochester Nair KS, US PA Danville Irving BA, US LA Baton Rouge Irving BA

Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Genetic knockout;overexpression, Exercise physiology;nutrition;life style Pathology: Obesity

Organism: Mouse, Rat Tissue;cell: Skeletal muscle, Nervous system, Liver, Fat Preparation: Permeabilized tissue

Coupling state: OXPHOS Pathway: N, S, NS HRR: Oxygraph-2k, TIP2k

Affiliations and author contributions

Brian Irving (1,2), Steve Roesch (2), Crystal Kane (1,2), Amanda Styer (2), George Argyropoulos (1,2)

(1) Geisinger Obesity Institute; Email: [email protected]

(2) Weis Center for Research, Geisinger Medical Center, Danville, PA

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 {{Abstract
-|title=Lund J, Hafstad AD, Hagve M, Larsen TS, Aasum E (2012) High intensity exercise prevents impairment of respiratory capacity in cardiac mitochondria from obese mice. MiPNet17.08.
+|title=Irving BA (2012) AgRP deficient female mice have elevated body weight and hypothalamic mitochondrial oxidative capacity. Mitochondr Physiol Network 17.13.
-|info=[[IOC68 Abstracts MiPNet17.08]]
+|info=[http://www.oroboros.at/?IOC-dec_schroecken IOC72 Open Access]
-|authors=Lund J, Hafstad AD, Hagve M, Larsen TS, Aasum E
+|authors=Irving BA
 |year=2012
-|event=IOC68
+|event=[[IOC72]]
-|abstract=Cardiac inefficiency and increased myocardial oxygen consumption are hallmarks of diabetes-induced cardiomyopathy, and is most likely related to ROS generation and mitochondrial dysfunction. We have recently shown that exercise prevent development of cardiac dysfunction and inefficiency. In the present study we investigated the effect of high intensity training (HIT) on mitochondrial respiration in cardiac mitochondria from obese mice. Because long chain fatty acids are supposed to increase LEAK oxygen consumption, experiments were performed both in the absence and presence of albumin-bound palmitate.
+|abstract=[[File:IMAG0127.jpg|right|200px|Brian Irving]]
+The central orexigenic agouti-related protein (AgRP) increases food intake when ubiquitously over expressed. Unexpectedly, AgRP deficiency also produces elevated food intake in female, but not male AgRP (-/-) mice. Moreover, the female AgRP (-/-) tend to be heavier than their wild type (WT) littermates.  We therefore examined whether differences in mitochondrial respiratory capacity and control could contribute to the propensity of the female AgRP (-/-) mice to eat more and gain more weight compared to their WT littermates. [[High-resolution respirometry]] was utilized to perform multiple substrate-inhibitor titration ([[SUIT]]) protocols designed to assess mitochondrial respiratory capacity and control in (mechanically and/or chemically) permeabilized hypothalamus, liver, skeletal muscle, and white adipose tissue acquired from female AgRP (-/-) and their WT littermates. In the hypothalamus, the female AgRP (-/-) mice had higher state-3 respiration (glutamate+malate+succinate+ADP) and higher maximally uncoupled respiration (FCCP) than their WT littermates.  However, there were no significant differences between groups for the respiratory control ratios in the hypothalamus. Likewise, there were no significant differences between groups for the O2 fluxes or respiratory control ratios in the liver, white adipose tissue, or gastrocnemius muscle. Similar to the present results, obese Zucker rats were reported to have enhanced mitochondrial oxidative capacity in the hypothalamus (1). In conclusion, AgRP deficiency in female mice results in elevations in hypothalamic mitochondrial oxidative capacity, likely contributing to their increased food intake and body weight.
-Methods: Diet-induced obese (DIO) mice were obtained by feeding C57BL/6J mice a high fat diet for 8 weeks. DIO mice were thereafter subjected to either a sedentary lifestyle (SED) or HIT (interval running, 10x4 min at 85-95% of ''V''<sub>O2max</sub>) for 8-10 weeks. Sedentary mice fed normal chow were included as lean controls (CON). Mitochondrial oxygen consumption was measured in isolated myocardial mitochondria (Oxygraph-2k, Oroboros Instruments) with glutamate and malate as substrates (5 and 2.5 mM, respectively). ADP (300 µM) was added to achieve maximal mitochondrial OXPHOS capacity (''P''). Mitochondrial LEAK oxygen consumption (''L'') was recorded after depletion of ADP and addition of oligomycin (4 µg/mL). In order to estimate the mitochondrial proton leak through the adenine nucleotide translocator (ANT), atractyloside (25 µM) was also added. The protocol was performed in the presence and absence of 75 μM palmitate.
+[1] [http://www.ncbi.nlm.nih.gov/pubmed?term=Enhanced%20hypothalamic%20glucose%20sensing%20in%20obesity%3A%20alteration%20of%20redox%20signaling Colombani AL, Carneiro L, Benani A, Galinier A, Jaillard T, Duparc T, Offer G, Lorsignol A, Magnan C, Casteilla L, Penicaud L, Leloup C (2009) Enhanced hypothalamic glucose sensing in obesity: alteration of redox signaling. Diabetes 58: 2189-2197 Open Access]
+|keywords=Orexins, Agouti-related protein, Obesity
-Results: ''P'' was reduced and ''L'' was increased in cardiac mitochondria from DIO mice. HIT was found to normalize ''P'' and to cause an increase in ''L''. Palmitate was found to increase ''L'' in all groups, although the latter response was less pronounced in mitochondria from HIT mice. Both basal and palmitate-dependent mitochondrial uncoupling was reduced by ANT inhibition.
+|mipnetlab=US MN Rochester Nair KS, US PA Danville Irving BA, US LA Baton Rouge Irving BA
-Conclusion: Diet-induced obesity is associated with a reduction in cardiac mitochondrial OXPHOS capacity, while mitochondrial uncoupling was unaltered. Exercise training restored respiratory capacity and increased uncoupling in isolated cardiac mitochondria from obese mice.  Exercise was also found to reduce the long chain fatty acid-induced uncoupling.
-|keywords=Exercise training, Respiration, Isolated mitochondria, Heart muscle, Obesity
-|mipnetlab=NO Tromso Larsen TS
 }}
 {{Labeling
-|instruments=Oxygraph-2k
+|area=Respiration, mt-Biogenesis;mt-density, Genetic knockout;overexpression, Exercise physiology;nutrition;life style
-|organism=Mouse
+|organism=Mouse, Rat
-|tissues=Cardiac muscle
+|tissues=Skeletal muscle, Nervous system, Liver, Fat
-|preparations=Isolated Mitochondria
+|preparations=Permeabilized tissue
-|topics=Coupling; Membrane Potential, Fatty Acid
+|diseases=Obesity
+|couplingstates=OXPHOS
+|pathways=N, S, NS
+|instruments=Oxygraph-2k, TIP2k
 }}
+__NOTOC__
+== Affiliations and author contributions ==
+Brian Irving (1,2), Steve Roesch (2), Crystal Kane (1,2), Amanda Styer (2), George Argyropoulos (1,2)
+(1) Geisinger Obesity Institute; Email: [email protected]
+(2) Weis Center for Research, Geisinger Medical Center, Danville, PA
+== Help ==
+* [[Abstracts IOC help]]
+* [[MitoPedia: Terms and abbreviations]]