Deletion of the brain-specific α and δ isoforms of adapter protein SH2B1 protects mice from obesity

Mice lacking SH2B1 and humans with inactivating mutations of SH2B1 display severe obesity and insulin resistance. SH2B1 is an adapter protein that is recruited to the receptors of multiple hormones and neurotrophic factors. Of the four known alternatively-spliced SH2B1 isoforms, SH2B1b and SH2B1g exhibit ubiquitous expression, whereas SH2B1a and SH2B1d are essentially restricted to the brain. To understand the roles for SH2B1a and SH2B1d in energy balance and glucose metabolism, we generated mice lacking these brain-specific isoforms (adKO mice). adKO mice exhibit decreased food intake, protection from weight gain on standard and high fat diets, and an adiposity-dependent improvement in glucose homeostasis. SH2B1 has been suggested to impact energy balance via the modulation of leptin action. However, adKO mice exhibit leptin sensitivity that is similar to that of wild-type mice by multiple measures. Thus, decreasing the abundance of SH2B1a and/or SH2B1d relative to the other SH2B1 isoforms likely shifts energy balance towards a lean phenotype via a primarily leptin-independent mechanism. Our findings suggest that the different alternatively-spliced isoforms of SH2B1 perform different functions in vivo.

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Deletion of the Brain-Specific α and δ Isoforms of Adapter Protein SH2B1 Protects Mice From Obesity

10.2337/figshare.13229090 ◽

2020 ◽

Author(s):

Jessica L. Cote ◽

Lawrence S. Argetsinger ◽

Anabel Flores ◽

Alan C. Rupp ◽

Joel M. Cline ◽

...

Keyword(s):

Energy Balance ◽

Adapter Protein ◽

Wild Type ◽

Leptin Sensitivity ◽

High Fat Diets ◽

Independent Mechanism ◽

Alternatively Spliced ◽

Fat Diets ◽

The Brain ◽

Inactivating Mutations

Mice lacking SH2B1 and humans with inactivating mutations of SH2B1 display severe obesity and insulin resistance. SH2B1 is an adapter protein that is recruited to the receptors of multiple hormones and neurotrophic factors. Of the four known alternatively-spliced SH2B1 isoforms, SH2B1b and SH2B1g exhibit ubiquitous expression, whereas SH2B1a and SH2B1d are essentially restricted to the brain. To understand the roles for SH2B1a and SH2B1d in energy balance and glucose metabolism, we generated mice lacking these brain-specific isoforms (adKO mice). adKO mice exhibit decreased food intake, protection from weight gain on standard and high fat diets, and an adiposity-dependent improvement in glucose homeostasis. SH2B1 has been suggested to impact energy balance via the modulation of leptin action. However, adKO mice exhibit leptin sensitivity that is similar to that of wild-type mice by multiple measures. Thus, decreasing the abundance of SH2B1a and/or SH2B1d relative to the other SH2B1 isoforms likely shifts energy balance towards a lean phenotype via a primarily leptin-independent mechanism. Our findings suggest that the different alternatively-spliced isoforms of SH2B1 perform different functions in vivo.

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Dissociation of obesity and insulin resistance in transgenic mice with skeletal muscle expression of uncoupling protein 1

Physiological Genomics ◽

10.1152/physiolgenomics.00194.2007 ◽

2008 ◽

Vol 32 (3) ◽

pp. 352-359 ◽

Cited By ~ 30

Author(s):

Yvonne Katterle ◽

Susanne Keipert ◽

Jana Hof ◽

Susanne Klaus

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Uncoupling Protein ◽

Wild Type ◽

Uncoupling Protein 1 ◽

Mitochondrial Uncoupling ◽

High Fat Diets ◽

Fat Diets ◽

White Fat

We evaluated the effect of skeletal muscle mitochondrial uncoupling on energy and glucose metabolism under different diets. For 3 mo, transgenic HSA-mUCP1 mice with ectopic expression of uncoupling protein 1 in skeletal muscle and wild-type littermates were fed semisynthetic diets with varying macronutrient ratios (energy % carbohydrate-protein-fat): HCLF (41:42:17), HCHF (41:16:43); LCHF (11:45:44). Body composition, energy metabolism, and insulin resistance were assessed by NMR, indirect calorimetry, and insulin tolerance test, respectively. Gene expression in different organs was determined by real-time PCR. In wild type, both high-fat diets led to an increase in body weight and fat. HSA-mUCP1 mice considerably increased body fat on HCHF but stayed lean on the other diets. Irrespective of differences in body fat content, HSA-mUCP1 mice showed higher insulin sensitivity and decreased plasma insulin and liver triglycerides. Respiratory quotient and gene expression indicated overall increased carbohydrate oxidation of HSA-mUCP1 but a preferential channeling of fatty acids into muscle rather than liver with high-fat diets. Evidence for increased lipogenesis in white fat of HSA-mUCP1 mice suggests increased energy dissipating substrate cycling. Retinol binding protein 4 expression in white fat was increased in HSA-mUCP1 mice despite increased insulin sensitivity, excluding a causal role in the development of insulin resistance. We conclude that skeletal muscle mitochondrial uncoupling does not protect from the development of obesity in all circumstances. Rather it can lead to a “healthy” obese phenotype by preserving insulin sensitivity and a high metabolic flexibility, thus protecting from the development of obesity associated disturbances of glucose homeostasis.

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Effects of Adrenalectomy on Energy Balance in Obese (ob/ob) Mice Fed High Carbohydrate or High Fat Diets

Journal of Nutrition ◽

10.1093/jn/117.6.1115 ◽

1987 ◽

Vol 117 (6) ◽

pp. 1115-1120 ◽

Cited By ~ 10

Author(s):

Colleen K. Grogan ◽

Hye-Kyung Kim ◽

Dale R. Romsos

Keyword(s):

Energy Balance ◽

High Fat ◽

High Carbohydrate ◽

High Fat Diets ◽

Fat Diets

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Rab27a Is an Essential Component of Melanosome Receptor for Myosin Va

Molecular Biology of the Cell ◽

10.1091/mbc.01-12-0595 ◽

2002 ◽

Vol 13 (5) ◽

pp. 1735-1749 ◽

Cited By ~ 124

Author(s):

Xufeng Wu ◽

Fei Wang ◽

Kang Rao ◽

James R. Sellers ◽

John A. Hammer

Keyword(s):

Full Length ◽

Tail Domain ◽

Wild Type ◽

Essential Component ◽

Myosin Va ◽

Alternatively Spliced ◽

Additional Protein ◽

The Brain ◽

Alternatively Spliced Exons

Melanocytes that lack the GTPase Rab27a (ashen) are disabled in myosin Va-dependent melanosome capture because the association of the myosin with the melanosome surface depends on the presence of this resident melanosomal membrane protein. One interpretation of these observations is that Rab27a functions wholly or in part as the melanosome receptor for myosin Va (Myo5a). Herein, we show that the ability of the myosin Va tail domain to localize to the melanosome and generate a myosin Va null (dilute) phenotype in wild-type melanocytes is absolutely dependent on the presence of exon F, one of two alternatively spliced exons present in the tail of the melanocyte-spliced isoform of myosin Va but not the brain-spliced isoform. Exon D, the other melanocyte-specific tail exon, is not required. Similarly, the ability of full-length myosin Va to colocalize with melanosomes and to rescue their distribution indilute melanocytes requires exon F but not exon D. These results predict that an interaction between myosin Va and Rab27a should be exon F dependent. Consistent with this, Rab27a present in detergent lysates of melanocytes binds to beads coated with purified, full-length melanocyte myosin Va and melanocyte myosin Va lacking exon D, but not to beads coated with melanocyte myosin Va lacking exon F or brain myosin Va. Moreover, the preparation of melanocyte lysates in the presence of GDP rather than guanosine-5′-O-(3-thio)triphosphate reduces the amount of Rab27a bound to melanocyte myosin Va-coated beads by approximately fourfold. Finally, pure Rab27a does not bind to myosin Va-coated beads, suggesting that these two proteins interact indirectly. Together, these results argue that Rab27a is an essential component of a protein complex that serves as the melanosome receptor for myosin Va, suggest that this complex contains at least one additional protein capable of bridging the indirect interaction between Rab27a and myosin Va, and imply that the recruitment of myosin Va to the melanosome surface in vivo should be regulated by factors controlling the nucleotide state of Rab27a.

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Selective Inactivation of Socs3 in SF1 Neurons Improves Glucose Homeostasis without Affecting Body Weight

Endocrinology ◽

10.1210/en.2008-0805 ◽

2008 ◽

Vol 149 (11) ◽

pp. 5654-5661 ◽

Cited By ~ 59

Author(s):

Ren Zhang ◽

Harveen Dhillon ◽

Huali Yin ◽

Akihiko Yoshimura ◽

Bradford B. Lowell ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Expenditure ◽

Glucose Homeostasis ◽

Leptin Resistance ◽

High Fat ◽

Leptin Signaling ◽

Leptin Sensitivity ◽

High Fat Diets ◽

Fat Diets

Suppressor of cytokine signaling 3 (Socs3) has been identified as a mediator of central leptin resistance, but the identity of specific neurons in which Socs3 acts to suppress leptin signaling remains elusive. The ventromedial hypothalamus (VMH) was recently shown to be an important site for leptin action because deleting leptin receptor within VMH neurons causes obesity. To examine the role of VMH Socs3 in leptin resistance and energy homeostasis, we generated mice lacking Socs3 specifically in neurons positive for steroidogenic factor 1 (SF1), which is expressed abundantly in the VMH. These mice had increased phosphorylation of signal transducer and activator of transcription-3 in VMH neurons, suggesting improved leptin signaling, and consistently, food intake and weight-reducing effects of exogenous leptin were enhanced. Furthermore, on either chow or high-fat diets, these mice had reduced food intake. Unexpectedly, energy expenditure was reduced as well. Mice lacking Socs3 in SF1 neurons, despite no change in body weight, had improved glucose homeostasis and were partially protected from hyperglycemia and hyperinsulinemia induced by high-fat diets. These results suggest that Socs3 in SF1 neurons negatively regulates leptin signaling and plays important roles in mediating leptin sensitivity, glucose homeostasis, and energy expenditure.

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Is food intake regulation based on signals arising in carbohydrate metabolism inherently inadequate for accurate regulation of energy balance on high-fat diets?

Behavioral and Brain Sciences ◽

10.1017/s0140525x00000327 ◽

1981 ◽

Vol 4 (4) ◽

pp. 581-583 ◽

Cited By ~ 4

Author(s):

J. P. Flatt

Keyword(s):

Energy Balance ◽

Food Intake ◽

Carbohydrate Metabolism ◽

High Fat ◽

High Fat Diets ◽

Food Intake Regulation ◽

Fat Diets ◽

Intake Regulation

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The brain needs interleukin-6 (IL-6) to maintain a “healthy” energy balance. Focus on “IL-6 ameliorates defective leptin sensitivity in DIO ventromedial hypothalamic nucleus neurons”

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00426.2016 ◽

2016 ◽

Vol 311 (6) ◽

pp. R989-R991 ◽

Cited By ~ 3

Author(s):

Thomas A. Lutz

Keyword(s):

Energy Balance ◽

Interleukin 6 ◽

Hypothalamic Nucleus ◽

Leptin Sensitivity ◽

Ventromedial Hypothalamic Nucleus ◽

The Brain

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Monobutyrin and Monovalerin Affect Brain Short-Chain Fatty Acid Profiles and Tight-Junction Protein Expression in ApoE-Knockout Rats Fed High-Fat Diets

Nutrients ◽

10.3390/nu12041202 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1202 ◽

Cited By ~ 1

Author(s):

Thao Duy Nguyen ◽

Frida Fåk Hållenius ◽

Xue Lin ◽

Margareta Nyman ◽

Olena Prykhodko

Keyword(s):

Tight Junction ◽

Hdl Cholesterol ◽

Short Chain ◽

Liver Cholesterol ◽

Tight Junction Proteins ◽

High Fat ◽

High Fat Diets ◽

Fat Diets ◽

The Brain ◽

Junction Proteins

Monobutyrin (MB) and monovalerin (MV), esters of short-chain fatty acids (SCFAs), have previously been shown to reduce liver cholesterol and inflammation in conventional rats fed high-fat diets. This study explored the potential effects of MB and MV in hypercholesterolemic apolipoprotein E-knockout (ApoE-/-) rats. ApoE-/- rats were fed three high-fat (HF) diets, pure or supplemented with MB or MV (1%), for 5 weeks. One group of conventional rats (C) was also fed the pure high-fat diet and another group of ApoE-/- rats a low-fat (LF) diet. Blood and liver lipids, urinary lactulose/mannitol, SCFAs (blood and brain), tight junction proteins (small intestine and brain), and inflammation-related markers (blood, brain, and liver) were analyzed. MV supplementation elevated serum high-density lipoprotein (HDL) cholesterol and valeric acid concentration (p < 0.05), while the amounts of isovaleric acid in the brain were reduced (p < 0.05). MB increased butyric acid amounts in the brain, while the plasma concentration of interleukin 10 (IL-10) was lowered (p < 0.05). Both MV and MB upregulated the expression of occludin and zonula occludens-1 (ZO-1) in the brain (p < 0.05). Supplementation of MB or MV affected HDL cholesterol, the expression of tight junction proteins, and SCFA profiles. MB and MV may therefore be promising supplements to attenuate lipid metabolic disorders caused by high-fat intake and genetic deficiency.

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