The interplay of glucose-dependent insulinotropic polypeptide in adipose tissue.

Adipose tissue was once known as a reservoir for energy storage but is now considered a crucial organ for hormone and energy flux with important effects on health and disease. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted from the small intestinal K cells, responsible for augmenting insulin release, and has gained attention for its independent and amicable effects with glucagon-like peptide 1 (GLP-1), another incretin hormone secreted from the small intestinal L cells. The GIP receptor (GIPR) is found in whole adipose tissue, whereas the GLP-1 receptor (GLP-1R) is not, and some studies suggest that GIPR action lowers body weight and plays a role in lipolysis, glucose/lipid uptake/disposal, adipose tissue blood flow, lipid oxidation, and free-fatty acid (FFA) re-esterification, which may or may not be influenced by other hormones such as insulin. This review summarizes the research on the effects of GIP in adipose tissue (distinct depots of white and brown) using cellular, rodent, and human models. In doing so, we explore the mechanisms of GIPR-based medications for treating metabolic disorders, such as type 2 diabetes and obesity, and how GIPR agonism and antagonism contribute to improvements in metabolic health outcomes, potentially through actions in adipose tissues.

Highland deer mice support increased thermogenesis in response to chronic cold hypoxia by shifting uptake of circulating fatty acids from muscles to brown adipose tissue.

During maximal cold challenge (cold-induced V̇O2,max) in hypoxia, highland deer mice (Peromyscus maniculatus) show higher rates of circulatory fatty acid delivery compared with lowland deer mice. Fatty acid delivery also increases with acclimation to cold hypoxia (CH) and probably plays a major role in supporting the high rates of thermogenesis observed in highland deer mice. However, it is unknown which tissues take up these fatty acids and their relative contribution to thermogenesis. The goal of this study was to determine the uptake of circulating fatty acids into 24 different tissues during hypoxic cold-induced V̇O2,max, by using [1-14C]2-bromopalmitic acid. To uncover evolved and environment-induced changes in fatty acid uptake, we compared lab-born and -raised highland and lowland deer mice, acclimated to either thermoneutral (30°C, 21 kPa O2) or CH (5°C, 12 kPa O2) conditions. During hypoxic cold-induced V̇O2,max, CH-acclimated highlanders decreased muscle fatty acid uptake and increased uptake into brown adipose tissue (BAT) relative to thermoneutral highlanders, a response that was absent in lowlanders. CH acclimation was also associated with increased activities of enzymes citrate synthase and ß-hydroxyacyl-CoA dehydrogenase in the BAT of highlanders, and higher levels of fatty acid translocase CD36 (FAT/CD36) in both populations. This is the first study to show that cold-induced fatty acid uptake is distributed across a wide range of tissues. Highland deer mice show plasticity in this fatty acid distribution in response to chronic cold hypoxia, and combined with higher rates of tissue delivery, this contributes to their survival in the cold high alpine environment.

Thermogenesis is supported by high rates of circulatory fatty acid and triglyceride delivery in highland deer mice.

Highland native deer mice (Peromyscus maniculatus) have greater rates of lipid oxidation during maximal cold challenge in hypoxia (hypoxic cold-induced V̇O2,max) compared with their lowland conspecifics. Lipid oxidation is also increased in deer mice acclimated to simulated high altitude (cold hypoxia), regardless of altitude ancestry. The underlying lipid metabolic pathway traits responsible for sustaining maximal thermogenic demand in deer mice is currently unknown. The objective of this study was to characterize key steps in the lipid oxidation pathway in highland and lowland deer mice acclimated to control (23°C, 21 kPa O2) or cold hypoxic (5°C, 12 kPa O2) conditions. We hypothesized that capacities for lipid delivery and tissue uptake will be greater in highlanders and further increase with cold hypoxia acclimation. With the transition from rest to hypoxic cold-induced V̇O2,max, both highland and lowland deer mice showed increased plasma glycerol concentrations and fatty acid availability. Interestingly, acclimation to cold hypoxia led to increased plasma triglyceride concentrations at cold-induced V̇O2,max, but only in highlanders. Highlanders also had significantly greater delivery rates of circulatory free fatty acids and triglycerides due to higher plasma flow rates at cold-induced V̇O2,max. We found no population or acclimation differences in fatty acid translocase (FAT/CD36) abundance in the gastrocnemius or brown adipose tissue, suggesting that fatty acid uptake across membranes is not limiting during thermogenesis. Our data indicate that circulatory lipid delivery plays a major role in supporting the high thermogenic rates observed in highland versus lowland deer mice.

Lipid oxidation during thermogenesis in high-altitude deer mice (Peromyscus maniculatus).

When at their maximum thermogenic capacity (cold-induced V̇o2max), small endotherms reach levels of aerobic metabolism as high, or even higher, than running V̇o2max. How these high rates of thermogenesis are supported by substrate oxidation is currently unclear. The appropriate utilization of metabolic fuels that could sustain thermogenesis over extended periods may be important for survival in cold environments, like high altitude. Previous studies show that high capacities for lipid use in high-altitude deer mice may have evolved in concert with greater thermogenic capacities. The purpose of this study was to determine how lipid utilization at both moderate and maximal thermogenic intensities may differ in high- and low-altitude deer mice, and strictly low-altitude white-footed mice. We also examined the phenotypic plasticity of lipid use after acclimation to cold hypoxia (CH), conditions simulating high altitude. We found that lipids were the primary fuel supporting both moderate and maximal rates of thermogenesis in both species of mice. Lipid oxidation increased threefold in mice from 30°C to 0°C, consistent with increases in oxidation of [13C]palmitic acid. CH acclimation led to an increase in [13C]palmitic acid oxidation at 30°C but did not affect total lipid oxidation. Lipid oxidation rates at cold-induced V̇o2max were two- to fourfold those at 0°C and increased further after CH acclimation, especially in high-altitude deer mice. These are the highest mass-specific lipid oxidation rates observed in any land mammal. Uncovering the mechanisms that allow for these high rates of oxidation will aid our understanding of the regulation of lipid metabolism.

Fuel Use in Mammals: Conserved Patterns and Evolved Strategies for Aerobic Locomotion and Thermogenesis.

SYNOPSIS: Effective aerobic locomotion depends on adequate delivery of oxygen and an appropriate allocation of metabolic substrates. The use of metabolic substrates during exercise follows a predictive pattern of lipid and carbohydrate oxidation that is similar in lowland native cursorial mammals. We have found that in two highland lineages of mice (Phyllotis and Peromyscus) the fuel use pattern is shifted to a greater reliance on carbohydrates compared to their lowland conspecifics and congenerics. However, there is variation between lineages in the importance of phenotypic plasticity in the expression of this metabolic phenotype. Moreover, this metabolic phenotype is independent of running aerobic capacity and can also be independent of thermogenic capacity. For example, wild-caught mice from a highland population of deer mice (Peromyscus maniculatus) housed in warm normoxic laboratory conditions maintain higher maximum cold-induced oxygen consumption in acute hypoxia than lowland congenerics, but shivering and non-shivering thermogenesis is supported by high rates of lipid oxidation. This is reflected in the consistently higher activities of oxidative and fatty acid oxidation enzymes in the gastrocnemius of highland deer mice compared to lowlanders, which are resistant to hypoxia acclimation. While a fixed trait in muscle aerobic capacity may reflect the pervasive and unremitting low PO2 at high altitudes, muscle capacities for substrate oxidation may be more flexible to match appropriate substrate use with changing energetic demands. How shivering thermogenesis and locomotion potentially interact in the matching of muscle metabolic capacities to appropriate substrate use is unclear. Perhaps it is possible that shivering serves as "training" to ensure muscles have the capacity to support locomotion or visa-versa.