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Homeostatic Responses to Acute Cold Exposure: Thermogenic Responses in Birds and Mammals

B. A. Horwitz

10.1002/cphy.cp040116

Source: Supplement 14: Handbook of Physiology, Environmental Physiology

Originally published: 1996

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Nonshivering vs. Shivering Pathways
1.1 Definitions and Distribution
1.2 Neural Control and Intracellular Sites of Heat Production
1.3 Contributions of NST Effectors and Shivering to Cold‐Induced Thermogenesis in Mammals and Birds
2 Sympathetic Activation of Brown Adipose Tissue
2.1 Alpha‐Adrenergic and Beta‐Adrenergic Involvement
2.2 Cellular Events Associated with Cold‐Induced Activation of Brown Adipocytes
3 Cold‐Induced Modification of NST by Agents Other than Catecholamines
3.1 Direct Effects on Thermogenic Mechanisms
3.2 Altered Release of Norepinephrine
3.3 Altered Delivery of Substrate/Oxygen
4 Summary and Future Directions
Figure 1. Figure 1.

Beta‐adrenergic thermogenic pathway in brown adipocytes—known events. Upon exposure to cold, norepinephrine released from sympathetic nerves interacts with β receptors in the plasma membrane. The resulting complex binds to the β subunit of the stimulatory G protein (Gs), to which a molecule of GTP is attached (not shown in diagram). Gs undergoes a conformational change, GTP is released, GDP binds, and the β subunit separates from the α subunit. The latter then binds to adenylate cyclase, activating it and enhancing the rate at which cyclic AMP (cAMP) is synthesized from ATP. cAMP activates protein kinase A (PKA), which phosphorylates hormone‐sensitive lipase, thereby activating it (HSL*). HSL* catalyzes the hydrolysis of triacylglycerol molecules stored in the lipid vacuoles within the adipocyte. Resulting free fatty acids (FFA) undergo rapid β‐oxidation in the mitochondria; most of the energy of oxidation is released as heat, and this heat is then transferred to the interstitial fluid and subsequently to the circulation. The rapid rate of fatty acid oxidation occurs because norepinephrine activation of this β‐adrenergic pathway also results in uncoupling of substrate oxidation from ATP synthesis via oxidative phosphorylation. Fatty acids may be involved in signaling this uncoupling (see text). Although not depicted in this diagram, alpha‐adrenergic receptors also respond to norepinephrine and contribute to the cold‐induced thermogenic response. As noted in the text, the events associated with the alpha response are not completely known. (Diagram is modified from that in ref. 81.)
Figure 2. Figure 2.

Schematic representation of the uncoupling mechanism underlying the rapid rates of substrate oxidation in norepinephrine‐activated brown adipocytes. A. When the brown adipocyte is not stimulated by norepinephrine, ATP synthesis is coupled to substrate oxidation as is the case in mitochondria in all other cells. As a result, when the cofactors (SH2) reduced during fatty acid oxidation are reoxidized by the electron transport chain, protons are transferred out of the mitochondrial matrix and return via the ATP synthetase, thereby linking substrate oxidation (respiration) to ATP synthesis. In this unactivated state, the proton conductance channel (unique to brown fat mitochondria) is closed. Current evidence indicates that this channel is formed by a dimer of the uncoupling protein, each dimer having a tripartite structure (represented by cylinders in the diagram), with one molecule of purine nucleotide (PN) binding per dimer. The PN binding site is thought to be exposed to the intermembrane space (and thus cytosol) 121. B. Cold exposure and the release of norepinephrine results in the generation of a cytosol signal that alters the conformation of the uncoupling protein, opening the proton channel and allowing protons to return to the mitochondrial matrix independent of ATP synthetase. This dissociates substrate oxidation from the slower process of ATP synthesis, allows fatty acids to be oxidized more rapidly, and allows heat to be generated at a faster rate. As discussed in the text, the cytosol signal triggering channel opening is still uncertain, although several of those proposed would act by displacing PN from its binding site on the dimer (as depicted in this diagram modified from that in ref. 81).


Figure 1.

Beta‐adrenergic thermogenic pathway in brown adipocytes—known events. Upon exposure to cold, norepinephrine released from sympathetic nerves interacts with β receptors in the plasma membrane. The resulting complex binds to the β subunit of the stimulatory G protein (Gs), to which a molecule of GTP is attached (not shown in diagram). Gs undergoes a conformational change, GTP is released, GDP binds, and the β subunit separates from the α subunit. The latter then binds to adenylate cyclase, activating it and enhancing the rate at which cyclic AMP (cAMP) is synthesized from ATP. cAMP activates protein kinase A (PKA), which phosphorylates hormone‐sensitive lipase, thereby activating it (HSL*). HSL* catalyzes the hydrolysis of triacylglycerol molecules stored in the lipid vacuoles within the adipocyte. Resulting free fatty acids (FFA) undergo rapid β‐oxidation in the mitochondria; most of the energy of oxidation is released as heat, and this heat is then transferred to the interstitial fluid and subsequently to the circulation. The rapid rate of fatty acid oxidation occurs because norepinephrine activation of this β‐adrenergic pathway also results in uncoupling of substrate oxidation from ATP synthesis via oxidative phosphorylation. Fatty acids may be involved in signaling this uncoupling (see text). Although not depicted in this diagram, alpha‐adrenergic receptors also respond to norepinephrine and contribute to the cold‐induced thermogenic response. As noted in the text, the events associated with the alpha response are not completely known. (Diagram is modified from that in ref. 81.)



Figure 2.

Schematic representation of the uncoupling mechanism underlying the rapid rates of substrate oxidation in norepinephrine‐activated brown adipocytes. A. When the brown adipocyte is not stimulated by norepinephrine, ATP synthesis is coupled to substrate oxidation as is the case in mitochondria in all other cells. As a result, when the cofactors (SH2) reduced during fatty acid oxidation are reoxidized by the electron transport chain, protons are transferred out of the mitochondrial matrix and return via the ATP synthetase, thereby linking substrate oxidation (respiration) to ATP synthesis. In this unactivated state, the proton conductance channel (unique to brown fat mitochondria) is closed. Current evidence indicates that this channel is formed by a dimer of the uncoupling protein, each dimer having a tripartite structure (represented by cylinders in the diagram), with one molecule of purine nucleotide (PN) binding per dimer. The PN binding site is thought to be exposed to the intermembrane space (and thus cytosol) 121. B. Cold exposure and the release of norepinephrine results in the generation of a cytosol signal that alters the conformation of the uncoupling protein, opening the proton channel and allowing protons to return to the mitochondrial matrix independent of ATP synthetase. This dissociates substrate oxidation from the slower process of ATP synthesis, allows fatty acids to be oxidized more rapidly, and allows heat to be generated at a faster rate. As discussed in the text, the cytosol signal triggering channel opening is still uncertain, although several of those proposed would act by displacing PN from its binding site on the dimer (as depicted in this diagram modified from that in ref. 81).

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Article Title: Homeostatic Responses to Acute Cold Exposure: Thermogenic Responses in Birds and Mammals
 

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B. A. Horwitz. Homeostatic Responses to Acute Cold Exposure: Thermogenic Responses in Birds and Mammals. Compr Physiol 2011, Supplement 14: Handbook of Physiology, Environmental Physiology: 359-377. First published in print 1996. doi: 10.1002/cphy.cp040116