cover of episode Best of: The future of exercise

Best of: The future of exercise

2025/1/3
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Russ Altman: 对谈围绕运动对人体生理的影响、减肥药的研发历程、以及未来研发‘运动药丸’的可能性展开。 Jonathan Long: 详细介绍了GLP-1受体激动剂类药物的研发历程,从80年代的基础科学研究到如今的成功应用,历时40年。最初用于治疗糖尿病,意外发现其具有减肥效果,经过优化后成为高效的减肥药物。 研究团队从化学角度研究运动,寻找与运动状态特异性相关的分子,以此理解复杂代谢过程。运动后产生的Lac-Phe分子具有抑制食欲的作用,且该分子在多种运动动物中都存在。内源性大麻素参与运动的动机调节。Lac-Phe由乳酸衍生而来,主要作用是通过肠-脑轴抑制食欲,可能还具有其他作用。训练有素的运动员和未经训练的个体对运动的代谢反应不同,这与他们代谢乳酸的能力有关。控制体重对于控制糖尿病至关重要,Lac-Phe可能通过使动物变瘦来间接改善糖尿病。Lac-Phe的研究处于早期阶段,类似于GLP-1药物在80年代的阶段,未来可能开发出基于Lac-Phe的减肥或抗糖尿病药物。减肥的关键在于减少脂肪量,同时保持肌肉量,但两者兼顾非常困难。将运动定义为药物需要更精确的分子水平定义,例如通过Lac-Phe水平区分不同强度的运动。运动和二甲双胍都能够刺激Lac-Phe通路,这揭示了二甲双胍减肥机制。‘运动药丸’的研发需要对运动通路有更深入的理解,这需要较长的时间。未来的‘运动药丸’可能包含多种成分,分别针对减肥、增肌和提升幸福感等不同目标。

Deep Dive

Key Insights

What is Lac-Phe, and what role does it play in the body after exercise?

Lac-Phe is a molecule derived from lactate, produced during high-intensity exercise. It suppresses appetite by signaling to the brain, which is why people often don't feel hungry after a hard workout. It is primarily produced in the gut and represents a gut-to-brain axis controlling feeding behaviors. Lac-Phe levels remain elevated for up to 12-18 hours after exercise, providing long-lasting physiological effects.

How does Lac-Phe differ in trained athletes versus untrained individuals?

Trained athletes have more efficient systems for metabolizing lactate, so their Lac-Phe levels do not spike as high after exercise. In contrast, untrained individuals experience a significant spike in both lactate and Lac-Phe levels, leading to a more pronounced effect of this pathway in untrained individuals.

What is the connection between Lac-Phe and diabetes?

Lac-Phe has been shown to help obese animal models lose weight, which in turn resolves diabetes. However, this effect is likely indirect, as weight loss improves overall metabolic health rather than Lac-Phe directly affecting glucose control systems.

Could Lac-Phe be the basis for a new weight loss drug?

Lac-Phe is a promising candidate for future weight loss drugs, but it is still in the early stages of research, similar to where GLP-1 drugs were in the 1980s. Further understanding of its pathway and mechanisms is needed before it can be developed into a therapeutic.

Why is it important to preserve lean muscle mass while losing weight?

Losing fat while preserving lean muscle mass is crucial because lean mass (muscle tissue) is essential for overall health and metabolic function. Losing muscle mass can negatively impact strength, metabolism, and long-term health. Resistance training is recommended to maintain lean mass during weight loss.

How does metformin relate to the Lac-Phe pathway?

Metformin, a diabetes drug, unexpectedly stimulates the Lac-Phe pathway. In fact, metformin is a stronger inducer of Lac-Phe than sprint exercise. This connection highlights how exercise and metformin converge on the same molecular pathways, providing a mechanism for metformin's weight loss effects.

What are the prospects for an 'exercise pill'?

An 'exercise pill' is a long-term goal that would require a deep understanding of the molecular pathways of exercise. Such a pill could benefit individuals who cannot exercise intensely, such as older adults. However, current research is still in its early stages, and it may take decades to develop such a therapeutic.

How does psychological preparation for exercise differ between humans and animals?

Psychological preparation for exercise is a complex and poorly understood area. In humans, motivation to exercise involves endocannabinoids, which are natural molecules that activate cannabinoid receptors in the brain. This system is less understood in animals, which may not plan exercise in the same way humans do.

Chapters
The recent surge in effective weight loss drugs, such as GLP-1 receptor agonists, is a result of decades of research. Initially used for diabetes treatment, these drugs showed modest weight loss, prompting further research and optimization, leading to the highly effective medications we have today.
  • GLP-1 receptor agonists' history goes back to the 1980s.
  • Initial use was for diabetes, with weight loss as an unexpected benefit.
  • Over 10 years of research led to significant weight loss without side effects.

Shownotes Transcript

Happy New Year! For many of us, a new year brings a renewed sense of motivation when it comes to health. Earlier this year, Russ sat down to speak with Jonathan Long), a Stanford biochemist who studies the chemicals produced during exercise. The conversation was one of our most popular during 2024 and today we’re re-sharing it. As many of us look to create healthy habits in 2025, we hope you’ll tune in to hear the exciting research Professor Long is doing to better understand the deep chemical connections between diet, exercise, and human health. 

Have a question for Russ? Send it our way in writing or via voice memo, and it might be featured on an upcoming episode. Please introduce yourself, let us know where you're listening from, and share your quest. You can send questions to [email protected]).

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Chapters:

(00:00:00) Introduction

Host Russ Altman introduces guest Johnathan Long, a professor of pathology at Stanford University.

(00:01:55)** Effective Weight Loss Drugs**

The history and development of GLP-1 receptor agonists.

(00:03:27)** Understanding Metabolism and Exercise**

The role of metabolic chemicals released during physical activity.

(00:05:02)** Animal Models in Exercise Studies **

The use of animal models in exercise studies and the discovery of Lac-Phe.

(00:06:40)** Psychological Preparation for Exercise **

The psychology of exercise preparation and the involvement of endocannabinoids.

(00:08:53) **Lac-Phe's Role and Mechanism **

Lac-Phe’s role in suppressing appetite and its production in the gut.

(00:11:46)** Differences in Exercise Response **

Exercise response between trained athletes and untrained individuals.

(00:12:50)** Diabetes and Metabolic Diseases **

The relationship between diabetes, exercise, and metabolic diseases.

(00:14:54)** Lac-Phe as a Potential Therapeutic **

Lac-Phe’s potential and parallels to the early stages of GLP-1 drug development.

(00:16:13)** Importance of How Weight is Lost **

The importance of losing fat while preserving lean muscle mass.

(00:19:04) **Exercise as Medicine **

The need to define physical activity at the same resolution as modern medicines.

(00:22:03) **Metformin and Exercise Pathways **

The unexpected connection between metformin and the Lac-Phe pathway.

(00:23:53) **Prospects of an Exercise Pill **

The future of an exercise pill, and challenges associated with its development.

(00:26:57)** Conclusion **

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